1-substituted-2-(phenyl or benzyl)-3- or 3 3 - piperidine(mono or dicarboxylic) acids and esters thereo fand octahydrobenzo(g) - quinolines and hexahydro-5h-inden (12-b)pyridines produced therefrom

ABSTRACT

1,2,3,4,4A,2,10,10A - OCTAHYDRO -5--(Y3)-5-(Y4)-BENZO (G)QUINOLINES AND 1,2,3,4,4A,-9B - HEXAHYDRO - 5- (Y3) -5(Y4) - 5H - INDENO (1,2-B)PYRIDES WHERIN Y3 AND Y4 ARE LOWER ALKYL OR PHENYL, WHICH ARE USEFUL AS ANTAGONIST OFR STRONG ANALGESICS, ARE OBTAINED BY LCYCLIZING DERIVATIVES OF 2 - (PHENYL OR BENZYL -A- (Y2) -A- Y4)-3-PIPERIDINEMETHANOLS. THE LATTER ARE OBTAINED FROM CORRESPONDING 3-PIPERIDINECARBOXYLIC ACIDS.

United States Patent l-SUBSTITUTED-Z-(PHENYL 0R BENZYL)-3- 0R 3,3PIPERIDINE(MON0 OR DICARBOXYLIC) ACIDS AND ESTERS THEREOF, AND OCTAHY-DROBENZO[g] QUINOLINES AND HEXAHY- DRO H INDENO[1,2-b]PYRIDINES PRODUCEDTHEREFROM 4 Noel F. Albertson, East Greenbush, and William F. Michne,Colonie, N.Y., assignors to Sterling Drug Inc., New York, N.Y. NoDrawing. Filed May 9, 1968, Ser. No. 728,044

Int. Cl. C07d 29/24 U.S. Cl. 260-29354 3 Claims ABSTRACT OF THEDISCLOSURE l,2,3,4,4a,5,10,l0a octahydro 5-(Y )-5-(Y benzo [g]quino1inesand l,2,3,4,4a,9b hexahydro 5 (Y )-5- (Y 5H indeno[l,2-b]pyridineswherein Y and Y are lower alkyl or phenyl, which are useful asantagonists of strong analgesics, are obtained by cyclizing derivativesof 2 (phenyl or benzyl) cc (Y oz (Y )-3-piperidinemethanols. The latterare obtained from corresponding 3-piperidinecarboxylic acids.

This invention relates to compositions of matter classified in the artof chemistry as benzo[g]quinolines and indeno[l,2-'b] pyridines, toprocesses for their preparation, and to intermediates for the same.

The invention sought to be patented resides in one composition aspect inthe concept of the novel chemical compounds designated asl,2,3,4,4a,5,10,10a-octahydro l-(Y )-7-(Y )-5-(Y )-5-(Y)-benzo[g]quinolines and as 1,2,3,4,4a,9b hexahydro 1 (Y 7 (Y 5 (Y 5 (Y5H indeno[1,2-b]pyridines having in the free base form the formulaFormula I wherein X is CH or a valence bond; Y is lower alkyl containing1-6 carbon atoms, 2,2-di (lower alkoxy) ethyl containing 4-6 carbonatoms, lower alkenyl containing 3-6 carbon atoms, lower alkynylcontaining 3-6 carbon atoms, halo-lower alkenyl containing 3-6 carbonatoms and one or two chlorine or bromine atoms attached to ethyleniccarbon, cyano-lower alkenyl containing 3-6 carbon atoms, cycloalkylcontaining 3-7 carbon atoms, cycloalkenyl containing 5-6 carbon atoms,dilower alkylcarbamyl containing 3-5 carbon atoms, and (Z)-lower alkylwherein lower alkyl contains l-3 carbon atoms and Z is phenyl,cycloalkyl containing 3-7 carbon atoms, and cycloalkenyl containing 5-6carbon atoms; Y is hydrogen, lower alkyl containing 1-4 carbon atoms,halo, trifiuoromethyl, nitro, hydroxy, lower alkoxy containing l-4carbon atoms, trihalomethoxy, alkanoyloxy containing 1-12 carbon atoms,cycloalkanecarbonyloxy containing 4-8 carbon atoms, pyridinecarbonyloxy,alkanoylamino containing 1-12 carbon atoms, and alkanesulfonamidocontaining 1-12 carbon atoms; Y and Y are the same or diiferent and arelower alkyl containing 1-4 carbon atoms, and phenyl.

3,639,411 Patented Feb. 1, 1972 These compounds are useful asantagonists of strong analgesics such as morphine and meperidine.

As will be appreciated, when X is the divalent methylene radical CHFormula I defines the 1,2,3,4,4a,5, 10,10a octahydro 1 (Y 7 (Y 5 (Y 5-(Y benzo[g]quinolines of this invention having in the free base form theformula Formula Ia And when X is a valence bond, Formula I defines the1,2,3,4,4a,9b hexahydro l (Y 7 (Y 5 (Y 5 (Y 5H indeno[1,2-b]-:Py'IldlIlS of this invention having in the free base form the formula)1 (in: if 34 2 Formula Ib When Y is lower alkyl there are included forexample methyl, ethyl, n-propyl, isopropyl, n-butyl, isoamyl, nhexyl,and the like. When Y is 2,2-di(lower alkoxy)ethyl there are included forexample 2,2-d'm1ethoxyethyl, 2,2- diethoxyethyl, and the like. When Y islower alkynyl there are included for example CECCH3,

-CECCH2CH3, CH CECCH CEO-CH(CH )CH and the like. When Y is loweralkenyl, there are included for example -CH CH=CHCH CH and the like.When Y is halo-lower alkenyl, there are included for example CBr=C(CH--CH CH=CCl CH CH -CH=CClCH and the like. When Y is cyano-lower alkenylthere are included for example and the like. When Y is cycloalkyl thereare included for example cyclopropyl, l-methylcyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and the like.

When Y is cycloalkenyl there are included for example, cyclopenten-Z-yl,cyclopenten-3-yl, l-methylcyclopentenl-yl, cyclohexen-Z-yl, and thelike. When Y is di-lower alkylcarbamyl there are includeddimethylcarbamyl and diethylcarbamyl. When Y is (Z)-lower alkyl thereare included for example benzyl, phenethyl, Z-phenylpropyl,cyclopropylmethyl, l-cyclopropylmethyl, 2-cyclopropylethyl,cyclohexylmethyl, 3-cyclopentylpropyl, cyclopenten- 1 ylmethyl,cyclopenten 2 ylmethyl, cyclohexen-2- ylmethyl,3-(cyc1ohexen-3-y1)propyl, and the like.

When Y is lower alkyl there are included for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, and the like. When Y is halothere are included chlorine, bromine, fluorine, and iodine. When Y islower alkoxy there are included for example methoxy, ethoxy, propoxy,isopropoxy, t-butoxy, and the like. When Y is trihalomethoxy there areincluded trichloromethoxy and trifluoromethoxy. When Y is loweralkanoyloxy there are included for example formoxy, acetoxy, propionoxy,isovaleroxy, dodecanoyloxy, and the like. When Y iscycloalkanecarbonyloxy, cyclobutanecanbonyloxy, cyclohexanecarbonyloxy,-1 methylcyclohexanecanbonyloxy, and the like. When Y ispyridinecarbonyloxy there are included 2- pyridinecarbonyloxy,3-pyridinecarbonyloxy, and 4-pyridinecarbonyloxy. When Y isalkanoylamino there are included for example formamido, acetamido,propionamido, isovaleramido, heptanoylamino, dodecanoylamino, and thelike. When Y is lower alkanesulfonamido there are included for examplemethanesulfonamido, ethanesulfonamido, hexanesulfonamido,octanesulfonamido, undecanesulfonamido, and the like.

When Y or Y is lower alkyl there are included for example methyl, ethyl,n-propyl, isopropyl, isobutyl, and the like.

The invention sought to be patented resides in One process aspect in theconcept of the process which comprises cyclizing a compound having inthe free base form the formula Y H larg f u Formula II or a compoundhaving in the free base form the formula 3 4 Y Y {e11 )0 Formula IIIwherein Y and Y have the same significance indicated in Formula I above,Y is hydrogen, lower alkyl containing 1-4 carbon atoms, halo,trifluoromethyl, and lower alkoxy containing 1-4 carbon atoms; and Q ishydrogen, lower alkyl containing 1-6 carbon atoms, aralkyl containing 7-10 carbon atoms, or acyl, by treatment with a strong organic orinorganic acid to yield a 1,2,3,4,4a,5,10,10aoctahydro 1-(Q)-7-(Y )-5-(Y)-5-(YO-benzo[g]quinoline or a 1,2,3,4,4a,9b-hexahydro-1-(Q)-7-(Y )-5-(Y)-5- (Y )-5H-indeno[1,2-b]Pyridine having in the free base form theformula Formula IV wherein X, Y Y Y and Q have the same significanceindicated above.

The invention sought to be patented resides in a further process aspectin the concept of the process which comprises interacting a compound ofFormula I except having H instead of Y with an agent having the formulaY -An, wherein Y has the same significance indicated in Formula I and Anis the anion of a strong organic or inorganic acid, in the presence ofan acid-absorbing medium, thereby forming a compound of Formula I.

The invention sought to be patented resides in a still further processaspect in the concept of the process which comprises interacting acompound of Formula I except having H instead of Y With an acid halideor acid anhydride of an acid having the formula M- COOH and reducing theresulting amide, 1,2,3,4,4a,5,10,10a-octahydro-1- (MCO)-7-(Y )-5-(Y)-5-(Y )-benzo[g]quinoline or 1,2,3,4,'4a,9b hexahydro 1-(MCO)-7-(Y)-5-(Y 5H-ind'eno[1,2-b]pyridine, with lithium aluminum hydride to yielda 1,2,3,4,4a,5,10,10a-octahydro-1-('MCH )-7- (Y )-5-(Y )-5-(Y)-benzo[g]quinoline or 1,2,3,4,4a,9bhexahydro 1 (MCH )-7-(Y )-5-(Y)-5-(Y )-5H-indeno[1,2-b]pyridine, wherein Y Y and Y have the samesignificance indicated in Formula I and M is the residual moiety inthose choices of Y which have the structural feature -CH directlyadjacent to, and attached to, the N atom in the 1-position of the benzo[g] quinolines or indeno[1,2-b]pyridines of Formula I.

The invention sought to be patented resides in a further compositionaspect in the concept of the 3-piperidinemethanols and the3-methylidenepiperidines represented respectively in the free base formby Formulas II and HI above which are useful intermediates in thepreparation of the benzo[g] quinolines and indeno[1,2-b]pyridines ofthis invention.

The invention sought to be patented resides in a still furthercomposition aspect in the concept of certain 2-substituted piperidines,more particularly identified hereinafter, hearing in the 3-position oneor two carboxy or carbo-lower alkoxy groups, which are useful asintermediates in the preparation of the above 3-piperidinemethanolintermediates.

The invention sought to be patented resides in the concept of severalfurther composition and process aspects as set forth hereinbelow.

Due to the presence of the basic amino grouping, the free base formsrepresented by Formulas I, Ia, Ib, iII, III, and IV above react withorganic and inorganic acids to form acid-addition salts. Theacid-addition salt forms are prepared from any organic or inorganicacid. They are obtained in conventional fashion, for instance either bydirect mixing of the base with the acid or, when this is notappropriate, by dissolving either or both of the base and the acidseparately in water or an organic solvent and mixing the two solutions,or by dissolving both the base and the acid together in a solvent. Theresulting acid-addition salt is isolated by filtration, if it isinsoluble in the reaction medium, or by evaporation of the reactionmedium to leave the acid-addition salt as a residue. The acid moietiesor anions in these salt forms are in themselves neither novel norcritical and therefore can be any acid anion or acid-like substancecapable of salt formation with the base.

Representative acids for the formation of the acid-addition saltsinclude formic acid, acetic acid, isobutyric acid,

5 alpha-mercaptopropionic acid, trifiuoroacetic acid, malic acid,fumaric acid, succinic acid, succinamic acid, tannic acid, glutamicacid, tartaric acid, oxalic acid, pyromucic acid, citric acid, lacticacid, glycolic acid, gluconic acid, saccharic acid, ascorbic acid,penicillin, benzoic acid, phthalic acid salicylic acid,3,5-dinitrobenzoic acid, anthanilic acid, cholic acid,2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphth0ic acid,picric acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituricacid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid,isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid,butylarsonic acid, methanephosphonic acid, acidic resins,

hydrofluoric acid, hydrochloric acid, hydrobromic acid,

hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoricacid, arsenic acid, and the like.

All of the acid-addition salts are useful as sources of the free baseform, by reaction with an inorganic base. It will thus be appreciatedthat if one or more of the characteristics, such as solubility,molecular weight, physical appearance, toxicity, or the like of a givenbase or acid-addition salt thereof render that form unsuitable for thepurpose at hand, it can be readily converted to another, more suitableform. For pharmaceutical purposes, acid-addition salts of relativelynon-toxic, pharmaceutically-acceptable acids, for example hydrochloricacid, lactic acid, tartaric acid, and the like, are of course employed.

The compounds of Formula I, as well as certain of the intermediates asindicated hereinbelow, can exist in sereochemically isomeric forms, thatis, optical isomers and geometric isomers. If desired, the isolation orthe production of a particular stereochemical form can be accomplishedby application of the general principles known in the prior art, and bythe methods herein described.

The manner and process of making and using the invention, and the bestmode contemplated by the inventors of carrying out this invention, willnow be described so as to enable any person skilled in the art to whichit pertains to make and use the same.

The process of this invention which comprises cyclizing a compound ofFormula II or III by treatment with a strong organic or inorganic acidis conveniently and readily effected by relatively mild reactiontemperatures, for instance, in the range 75l C. The preferred acid forthe cyclization is sulfuric acid, particularly in admixture with glacialacetic acid. However, other acids such as arylsulfuric acids or Lewisacids such as aluminum chloride are also satisfactory.

This cyclization process aifords direct-1y those species of Formula I,wherein Y is hydrogen, lower alkyl, aralkyl, or acyl, and Y is hydrogen,lower alkyl, halo, trifiuoromethyl, or lower alkoxy. These species aswell as those other sepcies of Formula I wherein Y is one of the otherchoices indicated in Formula I are obtained by interacting compounds ofFormula I except having H in place of Y with an alkylating agent havingthe formula Y An, wherein Y is as identified in Formula I An is theanion of a strong organic or inorganic acid, for instance a reactivehalide or an arylsulfonate, e.g. a methylbenzenesulfonate, in thepresence of an acid-absorbing medium, for instance an alkali metalcarbonate or bicarbonate, e.g. sodium bicarbonate, thereby afiording thedesired l,2,3,4,4a,5,10,10a octahydro-l-(Y )-7- (Y (Y )-5-(Y)-benzo[g]quinolines and l,2,3,4,4a,9b-hexahydro 1-(Y )-7-(Y )-5-(Y)-5-(Y )-5H-indeno[l,2-b]- pyridines.

When Y in these two groups of products has as a structural feature thedivalent methylene radical, CH at the point of attachment to thel-position nitrogen atom, for instance hexyl, cyclopropylmethyl, and thelike, a twostep indirect alkylation procedure can be employed. Thus, inthe first step the starting material of Formula IV, wherein Q ishydrogen, is N-acylated by treatment with an appropriate acid halide oracid anhydride of an acid having the formula M-COOH, preferably in thepresence of an acid-absorbing agent such as pyridine, thereby yieldingan amide product, l,2,3,4,4a,5,10,10a-octahydrol MCO) -7 (Y -5- (Y -5-(Y -benzo [g] quinoline or l,2,3,4,4a,9b-hexahydrol-(MCO-)7-(Y )-5-(Y5-(Y )-5H-indeno[1,2-b]pyridine. In the second step, the amide productof the first step is reduced with lithium aluminum hydride to yield thedesired 1,2,3,4,4a,5,10,10aoctahydro l-(MCH )-7-(Y )-5-(Y )-5-(Y )benzo[g]quinoline or 1,2,3,4,4a,9b-hexahydro-1-(M-CH 7-(Y )-5-(Y )-5-(Y)-5H-indeno[1,2-b1pyridine. [As will be appreciated, in each instance Mrepresents the residual moiety in those choices of Y as defined inFormula I which have the formula MCH Thus, for instance when Y is hexyl,M is CH -(CH and of course MCOOH is CH (CH COOH, MCO- is CH (CH -CO, andMCH is hexyl; and when Y is cyclopropylmethyl, M is cyclopropyl, and ofcourse MCOOH is cyclopropanecarboxylic acid, M-C0- iscyclopropanecarbony l, and MCH is cylopropylmethyl.

The species of Formula I where Y is hydroxy are obtained by cleaving thecorresponding alkoxy species with a suitable agent such as concentratedhydrobromic acid. By esterifying these hydroxy derivatives with asuitable O-alkanoylating or O-cycloalkanecarbonylating orO-pyridinecarbonylating agent there are obtained the species of FormulaI wherein Y is alkanoyloxy or cyoloalkanecarbonyloxy orpyridinecarbonyloxy respectively.

The species of Formula I wherein Y is nitro are obtained by nitratingthe corresponding species wherein Y is hydrogen. By reducing these nitrocompounds to the corresponding amino compounds and N-acylating them withalkanoylating or alkanesulfonylating agents there are obtained thespecies of Formula I wherein Y is alkanoylamino or alkanesulfonamido,respectively.

The species of Formula I wherein Y is trihalomethoxy are prepared fromthe corresponding methoxy compounds by methods generally old in the art;for example see Senning, Chemical Reviews, 65, 393-394 (1965).

The intermediate 2-substituted-3-piperidinemethanols of Formula H areconveniently obtained from 1-(Q)-2- [p-(Y)-phenyl-X]3,3-piperidinedicarboxylic acids, and lower alkyl estersthereof, wherein Q, Y and X have the same significance indicatedhereinabove, which form a further composition aspect of the instantinvention. These acids and their lower alkyl esters are obtained by thefollowing sequences of reactions of conventional type, both of whichstart with well-known and readily-available classes of compounds. Thus,when X is CH A di- (lower alkyl) 'Z-cyanoethylmalonate is acylated witha p-(Y )-phenylacetyl chloride to yield a di(lower alkyl) [p-(Y)-phenylacetyl] (2 cyanoethyl)malonate. Catalytic hydrogenation of thisproduct in the presence of platinum yields a di(lower alkyl) 2- [p-(Y)-benzyl]-3,3-piperidinedicarboxylate which is then interacted withbenzyloxycarbonyl chloride to yield di(lower alkyl)l-benzyloxycarbony1-2-[p-tY benzyl]-3,3-piperidinedicarboxylate. Bytreatment with an equimolecular proportion of alcoholic strong alkalithis diester is half-hydrolyzed to produce l-benzyloxycarbonyl-Z-[p-(Ybenzyl] 3 carbo- (lower alkoxy)-3-piperidinecarboxylic acid. When thisacid is heated to decarboxylate it, there is obtained a mixture of thecis and trans isomers of a lower alkyl l-benzyloxycarbonyl-2-[p-(Ybenzyl] 3 -piperidinecarboxylate. (The cis and trans forms are readilyseparable by fractional crystallization and the subsequent steps in thereaction sequence either the pure isomers or mixtures thereof, asdesired, can be employed.) When Y and Y are identical, these groups areintroduced in a Grignard reaction by treating the lower alkyll-benzyloxycarbonyl- 2-[p(Y )-benzyl]-3-piperidinecarboxylate with aGrignard reagent having the formula Y Mg-halogen, thus yielding a loweralkyl l-benzyloxycarbonyl-Z-[p-(Y benzyl]u,a-di(Y )-3-piperidinemethanolof Formula II wherein Q is benzyloxycarbonyl, and X is CH This productcan be used directly in the above-described cyclization process of thisinvention. Alternatively, the benzyloxycarbonyloxy can be removed bycatalytic hydrogenation in the presence of palladium catalyst to yield alower alkyl 2- [p- (Y -benzyl] -oL,o:-di (Y -3-piperidinemethanol ofFormula II wherein Q is hydrogen and X is -CI-I This product can be usedas such in the cyclization process or can be N-acylated, N-alkylated, orN-aralkylated to introduce Q groups other than hydrogen beforecyclization is effected.

When X in Formula II is a valance bond, the method of preparation ofthese intermediates is as follows: A lower alkyl [p-(Y5)-benzoyl]acetateis interacted with acrylonitrile in the presence of an alkali metalalkoxide to yield a lower alkyl a-[p-(Y )-benzoyl]-'y-cyanobutyrate,which is then catalytically hydrogenated in the presence of platinum toyield a lower alkyl 2-[p-(Y )-phenyl]-3-piperidinecarboxylate. Thisproduct is interacted with benzyloxycarbonyl chloride to yield a loweralkyl 1- benzyloxycarbonyl 2 [p-(Y )-phenyl]-3-piperidinecarboxylate.(In some instances, as specifically illustrated hereinbelow, theN-benzyloxycarbonylation step is not needed, and the Grignard reactioncan be successfully applied directly.) The further steps using thisproduct are the same as those described above for the corresponding 2-[p- (Y -benzyl] compounds.

When Y and Y in the intermediate 2-substituted-3- piperidinemethanols ofFormula H (and hence in the final products of Formula I) are unlike, thefollowing modification of the preparative method is used. A 2-[p-(Yphenyl-X]-3-piperidinecarboxylic acid is N-benzylated to yield al-benzyl-Z-[p-(Y )-phenyl-X]-3-piperidinecarboxylic acid. This productis interacted with lower alkyl lithium to yield 1-benzyl-2-[p-(Y)-phenyl-X] 3 (lower alkyl CO) -piperidine. By interacting this productin a Grignard reaction with a lower alkylmagnesium halide (wherein thelower alkyl is ditferent from lower alkyl in the lower alkyl COsubstituent) or phenylmagnesium halide there is obtained a 1-benzyl-2-[p-(Y )-phenyl-X-]- a-lower alkyl-u(lower alkyl orphenyl)-3-piperidinemethanol. The l-benzyl group is removed by catalytichydrogenation, thus yielding a 2- [p-(Y )-phenyl-X-]-a-lower alkyl-a-(lower alkyl or phenyl)-3-piperidinemethanol. This product is then usedin the same manner as described above for the corresponding productswherein the two a-substituents are alike.

When the cis form of the 2-substituted-3-piperidinemethanolintermediates of Formula II are cyclized in accordance with thisinvention, the benzo[g]quinoline or indeno[1,2-b] pyridine products of[Formula 'IV are almost wholly in the cis form. However, cyclization ofthe corresponding trans intermediates of Formula II yields the cis andthe trans forms of the benzo[g]quinolines or indeno[1,2-b]pyridines inproportions which vary according to the identity of the Q substituent.For example, when trans-2- (p-methoxybenzyl) -a,u-dimethyl 3piperidinemethanol was cyclized there was obtained the followingproportions of cis and trans forms of the 1,2,3,4,4a, 5,10,10a-octahydro1 (Q)-7-methoxy5,S-dimethylbenzo[g]quinoline:

Percent Q Cis Trans H 100 CH3 80 CuH4NO2-(p) -s 65 OHaC O 60SO2CsH4NO2(p)--- 80 20 Thus by appropriate choice of the Q substituent,the pro portion of the cis and trans cyclization products can beadjusted as desired.

Although the 2-substituted-3-piperidinemethanols of Formula II areordinarily the preferred intermediates, there can also be used thecorresponding olefin forms represented by Formula III, which appear inat least some instances to be formed during the'cyclization of thecompounds of Formula II. The 1-(Q)-2-[p-(Y )-phenyl-X-]- 3-[(Y )(Y)methylidene1piperidines of Formula. III wherein Q is benzyloxycarbonyl,are isolable as by-prodpets from the hydrogenolysis of thel-benzyloxycarbonyl- 2-[p-(Y )-phenyl-X-]-a-(Y )-a-(Y 3piperidinemethanols and can be cyclized as such or after removal of thebenzyloxycarbonyl group by hydrogenolysis followed, if desired, byN-alkylation, N-aralkylation, or N-acylation to introduce other Qgroups.

The structures of .the compounds of this invention were established bythe modes of synthesis, by elementary analysis, and by ultraviolet,infrared, and nuclear magnetic resonance spectra. The course of thereactions and homogeneity of the products were ascertained by thin layerchromatography.

The invention is illustrated by the following examples without, however,being limited thereto.

EXAMPLE 1 (A) A mixture of 53.3 g. of diethyl (2-cyanoethyl)- malonate,6.0 g. of sodium hydride, and 275 ml. of toluene was refluxed for fivehours, 250 ml. of toluene was then added and refluxing was continued fora further period of two hours. The mixture was then cooled below 5 C. inan ice bath and there was added dropwise a solution of 50.7 g. ofp-methoxyphenylacetyl chloride in ml. of toluene. After addition of theacid chloride was completed, the temperature of the reaction mixture wasallowed to rise to room temperature. The mixture was then stirred forone hour, diatomaceous silica filter aid (Filter-Cel-Johns-Manville) wasadded, and the mixture was filtered. The filtrate was concentrated underreduced pressure to yield 80.3 g. of a clear yellow oil. This oil wasfractionally distilled under reduced pressure. The fraction distillingat l69l74 C. at 0.4 mm. pressure weighed 12.6 g. and had n =1.4989. Thisproduct was diethyl (p methoxyphenylacetyl)-(2 cyanoethyl)- malonate.

(B) 10.8 g. of diethyl (p-methoxyphenylacetyl)-(2-cyanoethyl)malonatewas diluted with glacial acetic acid to a volume of 100 ml., 0.5 g. ofplatinum oxide was added, and catalytic hydrogenation at 50 poundshydrogen pressure was carried out for two and one-half hours, thetheoretical amount of hydrogen being absorbed during this period. Thehydrogenation mixture was filtered and the filtrate was concentratedunder reduced pressure. The resulting residue, which contained somecrystals, was partitioned between dilute hydrochloric acid and diethylether. The layers were separated, and after adding ice to the aqueouslayer it Was made basic by addition of ammonium hydroxide and extractedtwice with diethyl ether. The ethereal extracts were combined, washedwith water, and dried over anhydrous calcium sulfate, and etherealhydrogen chloride was added dropwise while cooling the mixture in an icebath. A somewhat gummy crystalline solid separated from solution. Afteradding a few milliliters of ethyl alcohol to dissolve away the gummymaterial the solid was collected on a filter, was washed with diethylether, and was dried at 70 C. The resulting product, which weighed 6.4g., was recrystallized twice from ethanoldiethyl ether to yield 4.9 g.of diethyl Z-(p-methoxybenzyl)-3,3-piperidinedicarboxylate hydrochlorideas a white crystalline solid which melted at 163-165 C.

(C) To a mixture of 252 g. of diethyl2-(p-methoxybenzyl)-3,3-piperidinedicarboxylate hydrochloride, 123 g. ofbenzyloxycarbonyl chloride, and 1200 ml. of chloroform there was addeddropwise g. of triethylamine while maintaining the temperature of thereaction mixture at approximately 25 C. by occasional cooling. After theaddition of triethylamine was complete, the reaction mixture was stirredfor one hour, then was washed successively with water, dilutehydrochloric acid, and a saturated aqueous solution of sodiumbicarbonate and dried over anhydrous calcium sulfate. The reactionmixture was filtered, and the filtrate was concentrated to yield 333 g.of diethyl 1 benzyloxycarbonyl 2- (p-methoxybenzyl)-3,3-piperidinedicarboxylate as a clear yellow oil.

(D) A mixture of 257 g. of diethyll-benzyloxycarbonyl-Z-(p-methoxybenzyl)-3,3-piperidinedicarboxylate, 35g. of 86 percent potassium hydroxide, 530 m1. of ethyl alcohol, and 530ml. of water was stirred and refluxed for seven and one-half hours. Thereaction mixture was concentrated under reduced pressure until onlywater distilled. More water was added to the reaction mixture, which wasthen extracted twice with diethyl ether. The ether extracts werecombined, washed with water, dried, filtered, and the filtrate wasconcentrated under reduced pressure to recover 108 g. of unhydrolyzeddiester starting material. The aqueous layers from the extractions werecombined and acidified with concentrated hydrochloric acid, causingseparation of an oil. This oil crystallized when shaken with a few ml.of diethyl ether. The mixture was filtered and the solid thus collectedwas washed with diethyl ether and air-dried. This product was a firstcrop of l-benzyloxycarbonyl2-(p-methoxybenzyl)-3-carbethoxy-3-piperidinecarboxylic acid. Byrepeating the hydrolysis procedure on the 108 g. of recovered diethyll-benzyloxycarbonyl 2 (p methoxybenzyl)-3,3-piperidinedicarbox ylate,using 14.6 g. of 86 percent potassium hydroxide, 225 ml. of ethylalcohol, and 225 ml. of water, there was obtained a second crop ofl-benzyloxycarbonyl-Z-(pmethoxybenzyl)-3-carbethoxy-3-piperidinecarboxylicacid. The two crops were combined and recrystallized from ethyl alcoholto yield 157 g. of this product as a white solid. When recrystallizedfiom ethyl alcohol, this compound melted at 186-l88 C. (dec.); IR (KBr)1650 cm? (urethane C=O).

(E) 157 g. of l-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-carbethoxy-3-piperidinecarboxylic acid was heated in an ethyleneglycol bath at 190-200 C. until gas evolution had ceased. The resultingproduct was cooled and dissolved in diethyl ether, and the ethersolution was washed with saturated aqueous sodium bicarbonate solution,dried, and filtered. The filtrate was concentrated by evaporation toyield 131 g. of clear, yellow syrup. This syrup was dissolved in 328 ml.of ethyl alcohol and the solution was cooled in a refrigeratorovernight. The white crystalline solid which separated from solution wascollected on a filter, washed with ethyl alcohol, and dried at 50 C.under reduced pressure. This product which weighed 80 g. and melted at68-71 C. was cis ethyl 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-piperidinecarboxylate. (The corresponding acid,cis-1-benzyloxycarbony1-2-(p-methoxybenzyl)-3-piperidinecarboxylic acid,was a white crystalline solid which melted at 174-175 C.)

The mother liquor from the above crystallization was concentrated underreduced pressure to yield 49 g. of a clear syrup consisting of atrans-rich mixture of the cis and trans forms of ethyll-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-piperidinecarboxylate.

By adding 1.0 ml. of concentrated hydrochloric acid to 6.05 g. of cisethyl 1-benzyloxycarbony1-2-(p-methoxybenzyl)-3-piperidinecarboxylate toconvetr the latter to its hydrochloride, diluting to a total volume of60 ml. with water, and catalytically hydrogenating in the presence ofpalladium-on-charcoal catalyst there was obtained 3.0 g. of cis ethyl2-(p-methoxybenzyl)-3-piperidinecarboxylate hydrochloride as a whitecrystalline solid which melted at l39l42 C. Similarly, 20.6 g. of atrans-rich mixture of the cis and trans forms of ethyl1-benzyloxycarbonyl-2-(p methoxybenzyl) 3 piperidinecarboxylatehydrochloride was catalytcially hydrogenated in the presence ofpalladium-on-charcoal catalyst to produce a trans-rich mixture of thecis and trans forms of ethyl 2-(p-methoxybenzyl)-3-piperidinecarboxylate hydrochloride. This salt (was converted to 10.4g. of the free base by treatment with ammonium hydroxide; and then thefree base was converted in ethyl acetate solution to thep-toluenesulfonate salt, which was isolated and recrystallized fromanhydrous 10 ethanol-diethyl ether to yield 6.8 g. of trans ethyl2-(pmethoxybenzyl 3 piperidinecarboxylate p-toluenesulfonate as a whitecrystalline solid which melted at 142 C.

Reduction of 8.2 g. of cis ethyl l-benpyloxycarbonyl-2-(p-methoxybenzyl-3-piperidinecarboxylate with 1.52 g. of lithiumaluminum hydride in 97 ml. of tetrahydrofuran yielded cis 1methyl-2-(p-methoxybenzyl)-3-piperidinemethanol, isolated as itshydrochloride (in a yield of 2.8 g.), white crystalline solid whichmelted at 185186 C. trans-l-methyl-2-(p-methoxybenzyl) 3piperidinemethanol, a white crystalline solid which melted at 66-68 C.,can be obtained in similar fashion.

(F) To a mixture of 7.2 g. of magnesium turnings and 75 m1. of anhydrousdiethyl ether there was gradually added a solution of 42.6 g. of methyliodide in 75 ml. of anhydrous diethyl ether at a rate suflicient tomaintain the reaction mixture at gentle reflux. When this addition wascompleted, the reaction mixture was stirred and refluxed for one hour,and then there was added in a fine stream a solution of 24.5 g. ofv cisethyl l-benzyloxycarbonyl-2-(p-methoxybenzyl) 3 piperidinecarboxylate in375 ml. of anhydrous diethyl ether. The resulting reaction mixture wasstirred and refluxed for three hours and then was poured into watercontaining 25 ml. of concentrated hydrochloric acid. More diethyl etherwas added, the mixture was shaken, and the ethereal layer was separated,washed with saturated aqueous sodium bicarbonate solution, dried, andfiltered. The filtrate was concentrated under reduced pressure to yield21.5 g. of cis-1- benzyloxycarbonyl-Z-(p-methoxybenzyl) u,ot dimethyl-3-piperidinemethanol as a syrup; IR (CHCl 3600 (free OH), 3450 (bondedOH), 1680 (C=O), 1250 and 1040 (ether), and 820 and 690 cm.- (1,4-diandmonosubstituted benzene).

Proceeding in the manner described above but using in place of the cisform, 49' g. of the trans-rich mixture of cis and trans ethyl1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-piperidinecarboxylate obtainedas described in the latter portion of part E, and using a Grignardreagent prepared by mixing 14.4 g. of magnesium turnings and ml. ofdiethyl ether with 85.1 g. of methyl iodide in 150 m1. of diethyl ether,there was obtained as the product 42.8 g. of a trans-rich mixture of cisand trans-l-benzyloxycarbonyl 2 (p -methoxybenzyl)-a, x-dimethyl-3piperidinemethanol as a syrup. The infrared spectrum of this product wasalmost identical with that of the cis product, minor diflerences beingobserved in the 1600 1000 cm.- region.

(G) 21.5 g. ofcis-l-benzyloxycarbonyl-Z-(p-methoxybenzyl)-u,a-dimethyl-3-piperidinemethanalwas mixed with 4.5 ml. of concentrated hydrochloric acid and dilutedwith 95 percent ethyl alcohol to a volume of 200 ml. This solution wassubjected to catalytic hydrogenation in the presence of 10 percentpalladium-on-charcoal catalyst for approximately two hours. The reactionmixture was filtered to remove the catalyst, and the filtrate wasconcentrated by evaporation under reduced pressure. The residue thusobtained was partitioned between water and diethyl ether. The aqueouslayer was made basic with ammonium hydroxide and extracted with diethylether. The ether extract was washed with water and dried over anhydrouscalcium sulfate. The ether extract was filtered and the filtrate wasconcentrated to yield 10.4 g. of cis-2-(p-methoxybenzyl)-a,wdimethyl-3-piperidinemethanol as a syrup. Asolution of this base in 90 ml. of ethyl acetate was mixed with 6.6 g.of p-toluenesulfonic acid hydrate in 60 ml. of ethyl acetate. The solidwhich formed was collected on a filter, washed with ethyl acetate, anddried at 50 C. overnight under reduced pressure. The product was thenrecrystallized from ethyl alcohol to yield 11.8 g. ofcis-2-(p-methoxybenzyl)-u,a-dimethyl 3 piperidinemethanolp-toluenesulfonate. This salt was a white solid which melted at 204206C. When 3.04 g. of this salt was treated with 0.5 ml. of acetyl chloridein the presence of 2.0 m1. of triethylamine in 60 m1. of chloroformthere was obtained 1.1 g. of cis-1-acetyl-2-(p-methoxybenzyl)-a,u-dimethyl-3-piperidinemethanol as a white crystalline solid whichmelted at 13 8140 C.

190 g. of trans-rich mixture of cisandtrans-l-benzyloxycarbonyl-2-(p-methoxybenzyl-a,a-dimethyl 3piperidinemethanol obtained in the manner described above in the latterportion of part F was mixed with 40 ml. of concentrated hydrochloricacid and 5 g. of palladium-on-charcoal catalyst, and the resultingmixture was diluted to a volume of 1800 ml. with 95 percent ethylalcohol. This mixture was hydrogenated under a hydrogen pressure of 435pounds per square inch for seven hours, hydrogen consumption ceasedafter four hours. The reaction mixture was filtered through Filter- Celusing a small quantity of 95 percent ethyl alcohol as a rinse. Thecombined filtrate and rinse was evaporated dryness under reducedpressure. The residue was partitioned between water and diethyl ether,and the aqueous layer was made basic with concentrated ammoniumhydroxide and extracted with ether. The ether extract was washed withwater, dried, filtered, and evaporated to dryness under reduced pressureto give 93 g. of syrupy product. This material was taken up in 500 ml.of diethyl ether and slowly treated with 170 ml. (one equivalent) of 2 Nethanolic hydrogen chloride. The resulting solution was cooled forseveral hours at 0 C. to give, after filtration and washing with ether,43 g. of trans-Z-(p-methoxybenzyl) 04,0: dimethyl-3-piperidinemethanolhydrochloride which melted at 156-159 C. After recrystallization, thisproduct melted at 158-159 C., R .42 (silica, CHCl 3% isopropyl amine),mixture with cis isomer showed two spots, R .38 and .42; IR (KBr) 1250and 1030 (ether) and 820 cm.- (1,4- disubstituted benzene), When 1.8 g.of this salt was treated with 0.43 ml. of acetyl chloride in thepresence of 1.68 ml. of triethylamine in 18 n11. of chloroform there wasobtained 1.4 g. oftrans-1-acetyl-2-(p-methoxybenzyl)-a,u-dimethyl-3-piperidinemethanol asa white crystalline solid which melted at 111-113 C.

Interaction of 3.04 g. ofcis-2-(p-methoxybenzyl)-a,adimethyl-3-piperidinemethanolp-toluenesulfonate with 1.55 g. of p-nitrobenzenesulfonyl chloride atroom temperature in a mixture of 2.0 ml. of triethylamine and 60 ml. ofchloroform yielded 2.2 g. ofcis-l-(p-nitrobenzenesulfonyl)-2-(p-methoxybenzyl) a, dimethyl-3-piperidinemethanol as a yellow solid which melted at 182-184 C. Insimilar fashion, interaction of 2.20 g. of trans-2-(p-methoxybenzyl)-11,dimethyl-3-piperidinemethanol hydrochloride with 1.62 g. ofp-nitrobenzenesulfonyl chloride at room temperature in a mixture of 2.1ml. of triethylamine and ml. of chloroform yielded 2.55 g. oftrans-1-(p-nitrobenzenesulfonyl)-2-(p-methoxybenzyl)-a,a-dimethyl-3-piperidinemethanolas a yellow solid which melted at 132l34 C.

A mixture of 2.2 g. of trans-2-(p-methoxybenzyl)-a,a-dimethyl-3-piperidinemethanol hydrochloride, 0.65 ml, of 35 aqueousformaldehyde solution, and 1.1 ml. of triethylamine was diluted to atotal volume of ml. with ethanol and catalytically hydrogenated in thepresence of palladium-on-charcoal catalyst. From the resulting reactionmixture there was obtained 1.0 g. oftrans-1,a,a-trimethyl-2-(p-methoxybenzyl) 3-piperidinemethanol as awhite crystalline solid which melted at 78-79 C. In similar fashion,catalytic hydrogenation of a mixture of 2.6 g. ofcis-2-(p-methoxybenzyl)-a,adimethyl-3-piperidinemethanol and 0.75 ml. of35% aqueous formaldehyde solution in ethanol yielded 1.4 g. ofcis-1,a,a-trimethyl-2-(p-methoxybenzyl)-3-piperidinemethanol as anoff-white crystalline solid which melted at 9496 C.

(H) A mixture of 8.0 g. of cis-2-(p-methoxybenzyl)a,a-dimethyl-3-piperidinemethanol p-toluenesulfonate, 65 ml.-of glacialacetic acid, and 13 ml, of concentrated sulfuric acid was heated on asteam bath for ten minutes,

12 poured into water made basic with concentrated ammonium hydroxide,and extracted with ether. The extract was washed with water, dried,filtered, and evaporated to dryness under reduced pressure to give 3.6g. of crude product. A thin layer chromatogram (alumina, chloroform/ 5methanol) showed the major product at R =.18 and a faint trace at R=.50. The residue was taken up in ether and treated with a slight excessof ethanolic hydrogen chloride. The hydrochloride which precipitated wasrecrystallized from 95 percent ethyl alcohol. This product, which wascis-1,2,3,4,4a,5,10,10aoctahydro-7-methoxy-5 ,5 -dimethylbenzo [g]quinoline hydrochloride melted at 225 C.; IR (KBr) 1250 and 1050 (ether)and 870 and 800 cmr (1,2,4substituted benzene); NMR (of base, CDCl420-390 (In. 3), 223 (s. 3) 78, 73 (singlets, 6 total), 220-50 (broadenvelope, 11).

A mixture of 4.5 g. of trans-2-(p-methoxybenzyl)-u,a-dimethyl-3-piperidinemethanol hydrochloride, 25 ml. of glacialacetic acid, and 5 ml. of concentrated sulfuric acid was heated on asteam bath for twelve minutes, poured into water, made basic withconcentrated ammonium hydroxide, and extracted with ether. The extractwas washed with water, dried, filtered, and evaporated to dryness underreduced pressure to give 3.2 g. of product. A thin layer chromatogram(alumina, chloroform/5% methanol) showed a faint trace at R,=.18 withthe major component at R;=.50. The residue was taken up in diethyl etherand treated with a slight excess of ethanolic hydrogen chloride. Thehydrochloride which precipitated was recrystallized from 95 percentethyl alcohol. This product, which was trans-1,2,3,4,4a,5,10,10a-0ctahydro 7-methoxy-5,5 dimethylbenzo[g] quinolinehydrochloride, melted at 295298 C.; IR. (KBr) 1240 and 1040 (ether) and860 and 830 cm.- (1,2,4trisubstituted benezene; NMR (of base, CD01420-390 (mm, 3), 224 (s. 3), 78 and 67 (singlets, 3 each) 200-50 (broadenvelope, 11).

Interaction of 2.20 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-7-methoxy5,5 dimethylbenzo[g] quinoline hydrochloride with 1.73 g. ofp-nitrobenzenesulfonyl chloride at room temperature in a mixture of 2.2m1. of triethylamine and 40 ml. of chloroform yielded 2.77 g. of cis-1,2,3,4,4a,5,10,10a-octahydro 1(p-nitrobenzenesulfonyl)-7-methoxy-5,S-dimethylbenzo[g]quinoline as ayellow solid which melted at 176-178 C. Similarly, us-

ing the trans form of the starting material in this acylation, there wasobtained 2.03 g. of trans-1,2,3,4,4a,5,10, 1'0a-octahydro 1(p-nitrobenzenesulfonyl)-7-methoxy- 5,5-dimethylbenzo[g] quinoline as anoff-white solid which melted at 203-205" C.

EXAMPLE 2.

(A) Cis-1,2,3,4,4a,5,10,10a-octahydro 7 methoxy- 5,5-dimethylbenzo[g]quinoline hydrochloride was treated with dilute ammonium hydroxide, andthe free base thus obtained was dried in ether. After filtration andevaporation of the solvent under reduced pressure, the residue whichweighed 0.7 g. was mixed with 2 m1. of formic acid and 2 m1. of 35%aqueous formaldehyde solution and the mixture was heated on a steam bathfor one and onehalf hours. The reaction mixture was diluted with water,made basic with concentrated ammonium hydroxide and extracted withdiethyl ether. The ether extract was washed with water, dried, filtered,and evaporated to dryness under reduced pressure. The residue (0.7 g.)was distilled, B.P. (0.03 mm.) 110 C.; IR (thin film) 1240 and 1050(ether) and 870 and 800 (1,2,4-trisubstituted benzene); NMR (ODCl 224-(s. 3), '(s. 3). 79 and 74 (singlets, 3 each). This product wascis-1,2,3, 4,4a,5,10,l0a-octahydro 7 methoxy-l,5,5-trimethylbenzo [g]quinoline.

A mixture of 2.0 g. of this base, 1.2 g. of methyl iodide, and 20 ml. ofacetonitrile was allowed to stand at room temperature. Crystallizationoccurred within one hour. After cooling the mixture in ice for severalhours, there 13 was obtained 2.7 g. ofcis-1,2,3,4,4a,5,10,10a-octahydro-7-methoxy-l,5,S-trimethylbenzo[g]quinoline methiodide, M.P. 286 C.(dec.). Recrystallization from water brought the melting point of thisproduct to 2-88-293 C. (dec.).

(B) Using the same manipulative procedure as that described in part A,5.6 g. of trans-l,2,3,4,4a,5,10,10aoctahvdro-7-methoxy 5,5dimethylbenzo[g]quinoline hydrochloride was treated with dilute ammoniumhydroxide to yield 4.9 g. of the corresponding free base which wastreated with formic acid and 35% aqueous formaldehyde solution to yield5.0 g. of crude product which was distilled. There was thus obtainedtrans-1,2,3, 4,4a,5,l0,10a-octa hydro 7methoxy-1,5,5-trimethylbenzo[g]quinoline as a clear liquid, B.P. (0.02mm.) 120 C.; IR (film) 850 and 790 cmr 1,2,4-trisubstituted benzene);NMR (CDCI 221 (s. 3), 138 (s. 3), 78 and 65 (singlets, 3 each). A 0.7 g.portion of this base was interacted with 0.7 g. of methyl iodide inacetonitrile to yield 0.95 g. of the methiodide, M.P. 301305 C. (dec.).

EXAMPLE 3 A mixture of 3.0 g. ofcis-1,2,3,4,4a,5,10,10a-ctahydro-7-methoxy 5,5 dirnethylbenzo[g]quinoline -hydrochloride, 1.8 g. of n-propyl iodide, 2.5 g. of sodiumbicarbonate, and 40 ml. of dimethylformamide was stirred and refluxedfor three hours. The reaction mixture was concentrated under reducedpressure and the resulting residue was partitioned between water anddiethyl ether. The ether layer was washed with water, dried, treatedwith decolorizing charcoal, and filtered, and the filtrate wasconcentrated to yield 2.5 g. of a syrup. This product, a base, wastreated with ethanolic hydrogen chloride and the resulting basehydrochloride was recrystallized and converted back to the free base bytreatment with aqueous sodium hydroxide solution to yield 1.3 g. ofcis-l,2,3,4, 4a,5,10,10a-octahydro 1 propyl 7methoxy-5,5-dimethylbenzo[glquinoline as a syrup. This base wasdissolved in a mixture of chloroform and methanol and chromatographed on130 g. of alumina, eluting with chloroform. The base thus obtained wasconverted to the hydrochloride (0.8 g.) by treatment with ethanolichydrogen chloride. Recrystallization of this product fromethanol-diethyl ether yielded 0.7 g. of cis-l,2,3,4,4a,5,10,10a-octahydro 1 propyl-7-methoxy-5,S-dimethylbenzo [g]quinolinehydrochloride as a white crystalline solid which melted at 201-202" C.

EXAMPLE 4 A mixture of 0.56 g. ofcis-l,2,3,4,4a,5,10,10a-octahydro-7-methoxy 5,5dimethylbenzo[g]quinoline hydrochloride, 0.27 g. of sodium acetatetrihydrate, and 7 ml. of acetic anhydride was stirred and heated on asteam bath for three hours. The reaction mixture was evaporated todryness under reduced pressure, and the resulting residue waspartitioned between water and diethyl ether. The ether layer was washedwith 1 N-hydrochloric acid and with saturated aqueous sodium bicarbonatesolution. After drying the ethereal solution, filtering, and removingthe solvent by evaporation under reduced pressure, there was obtained0.52 g. of a syrup which crystallized from hexane to yieldcis-1-acetyl-1,2,3,4,4a,5,10,10aoctahydro 7methoxy-5,5-dimethylbenzo[g]quinoline, M.P. 8 1-85 C.; IR (OHCl 1630cm.- (C O); NMR (CDCl 80 (s. 3), 78 (s. 3).

In similar fashion 1.06 g. of trans-1,2,3,4,4a,5,10,10aoctahydro 7methoxy-5,5-dimethyl-benzo[g]quinoline hydrochloride Was N-acetylated toyield 1. 0 g. of trans-1- acetyl-1,2,3,4,4a,5,l0,10a-octahydro 7methoxy-5,5-dimethyl benzo[g]quinoline M.P. l57159 C.; IR (CHCI 1630CIHF'I (0:0); NMR (CHCI 80 (s. 3), 68 (s. 3).

14 EXAMPLE 5 A mixture of 2.2 g. ofcis-l,2,3,4,4a,5,10,10a-octahydro-7-methoxy 5,5dimethyl-benzo[g]quinoline hydrochloride, 1.73 g. ofp-nitrobenzenesulfonyl chloride, 40 ml. of chloroform and 2.2 ml. oftriethylamine was allowed to stand for twenty-four hours at roomtemperature. The reaction mixture was then washed successively with a 40ml. portion each of water, 1 N-hydrochloric acid, and saturated aqueoussodium bicarbonate solution. After drying, filtration, and evaporationof the solvent under reduced pressure, there was obtained 3.4 g. ofcrude product. This was dissolved in 10 ml. of warm chloroform, dilutedwith 60 ml. of hot ethanol, and cooled. The product was filtered, washedwith ethanol, and dried at 50 C. under reduced pressure to give 2.8 g.of cis-l-(p nitrobenzenesulfonyl)-1,2,3,4,4a,5,10,10aoctahydro-7-methoxy5,5 dimethylbenzo[g]quinolnie, M.P. 176178 C; IR (KBr) 1530 and 1350cm." (N02), 1350 and 1160 (S0 N'MR (OD-C1 489 (A B 4), 223 (s. 3), 75and 77 (singlets, 6).

In similar fashion, 3.0 g. oftrans-1,2,3,4,4a,5,10,10aoctahydro-7-methoxy-5,5-dimethylbenzo [g]quinoline hydrochloride was converted totrans-1-(p-nitrobenzenesulfonyl) 1,2,3,4,4a,5,10,10a octahydro 7methoxy-5,5- dimethylbenzo[g]quinoline, M.P. 203205 C.; IR (KBr) 1530and 1350 (N0 and 1350 and 1160 (S0 NMR (CDCI 487 (A B ,4), 224 (s.3), 76and 60 (singlets, 3 each).

EXAMPLE 6 Interaction of 15.1 g. of crude 2-(p-methoxybenzyl)-a,a-dimethyl-3-piperidinemethanol with 10.9 g. of p-toluenesulfonylchloride in ml. of pyridine yields 15.9 g. of 1- (p-toluenesulfonyl) 2(p-methoxybenzyl)-ot,u-dimethyl-3-piperidinemethanol as a red syrup.Proceeding in a manner similar to that described above in part H ofExample 1, 14.5 g. of this red syrup was heated with a mixture of 75 ml.of glacial acetic and 15 ml. of concentrated sulfuric acid to yield 3.3g. of crude 1,2,3,4,4a,5,l0,10aoctahydro 1 (p-toluenesulfonyl) 7methoxy-5,5-dimethylbenzo[ g] quinoline as a light brown solid whichmelted at 112115 C. By chromatographing this product on alumina, using ahexane and chloroform mixture in volume/volume ratio of 75/25, there wasobtained 1.9 g. ofcis-1,2,3,4,4a,5,10,10a-octahydro-1-(p-toluenesulfonyD-7-methoxy-5,5-dimethylbenzo[g]quinoline as a white crystalline solidwhich melted at 130-133 C. The corresponding trans compound, obtained ina yield of 2.7 g. by interacting 4.2 g. oftrans-l,2,3,4,4a,5,10,10a-octahydro-7-methoxy-5,5-dimethylbenzo[g]quinolinewith 2.9 g. of p-toluenesulfonyl chloride in the presence of 50 ml. ofpyridine, was a white crystalline solid which melted at -167 C EXAMPLE 7A solution of 71.4 g. of a crude mixture of cisand trans-1,2,3,4,4a,5,10,10a octahydro 7 methoxy 5,5 dimethylbenzo[g] quinoline(determined by nuclear magnetic resonance spectral measurement tocontain approximately 60% of the cis isomer) in 700 ml. of 48%hydrobromic acid was refluxed for one and one-half hours and allowed tocool slowly. This caused crystallization of 47.4 g. ofcis-1,2,3,4,4a,5,10,10a octahydro 5,5 dimethylbenzo [g]quinolin-7-olhydrobromide. This was recrystallized from methanol-ether to give 41.5g. of this product which melted at 333-33 6 C.

Slow evaporation of the mother liquor from the first crystallizationunder reduced pressure caused crystallization of 14.1 g. oftrans-l,2,3,4,4a,5,10,10aoctahydro-5,5- dimethylbenzo[g] quinolin-7-olhydrobromide. 'Ihis product melted at 294298 C. after recrystallizationfrom methanol-ether.

The cis base was obtained by stirring a suspension of 41.5 g. of the cishydrobromide in 400 ml. of water and 100 ml. of concentrated ammoniumhydroxide-on a steam bath for one-half hour, cooling, and filtering.After wash- 15 ing with water and drying to constant weight, there wasobtained 29.4 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[g]quinolin-7-ol. After a recrystallization from ethanol,this base melted at 2l4216 C.; (nmr DMSO d methyl singlets at 72 and 68Hz.

The trans base was similarly obtained from the trans hydrobromide in 92%yield; nmr (DMSO-d methyl singlets at 72 and 60.

EXAMPLE 8 A mixture of 2.31 g. ofcis-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[g]quinolin-7-ol. 1.0g. of 35% aqueous formaldehyde solution, and 0.2 g. ofpalladium-on-carbon catalyst was diluted to 100 ml. total volume withethanol and shaken under 50 p.s.i. of hydrogen at room temperature. Thetheoretical quantity of hydrogen was consumed in three hours. Thereaction mixture was filtered and the filtrate was evaporated underreduced pressure at room temperature. There was thus obtained 1.1 g. ofcis 1,2,3,4,4a,5,10,10a octahydro 1,5,5 trimethylbenzo[g]quinolin-7-olas a white crystalline solid M.P. 204207 'C.; nmr (TFAA) showed methylsinglets at 86 and 78 Hz.

In similar fashion, trans compound was prepared in exactly the samemanner as the corresponding cis compound. Thus, 2.0 g. oftrans-1,2,3,4,4a,5,10,10a-octahydro-1,5,5-trimethylbenzo[g]quinolin-7-ol as a white crystalline solid, M.P.270-272 C.; nmr (TFAA) showed methyl singlets at 86 and 72 Hz.

EXAMPLE 9 A mixture of 3.5 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo [g]quinolin-7-ol, 1.7 g. of sodium bicarbonate, 40 ml.of dimethylformamide, and 219 g. of npropyl iodide was stirred andrefluxed for three hours and evaporated to dryness under reducedpressure. The residue was partitioned between water and diethyl ether.The other layer was washed with water, dried, filtered, and treated witha slight excess of ethanolic hydrogen chloride. The supernatant liquidwas decanted from the gum which precipitated, and the gum was dissolvedin a small quantity of ethanol. Dilution with ether causedcrystallization of 3.5 g. of solid, M.P. 263266 C. Recrystallization ofthis solid from ethanol-ether gave 3.15 g. of cis-1,2,3,4,4a,5,10,10a-octahydro 1 propyl 5,5 dimethylbenzo- '[g] quinolin-7-olhydrochloride as an ofl-white crystalline solid, M.P. 264-266 C.; nmr(DMSO-d methyl singlets at 74 and 70 Hz.

A mixture of 2.3 g. oftrans-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[g]quinolin-7-ol,0.8 g. of sodium bicarbonate, 30 ml. of dirnethylformamide, and 1.7 g.(0.01 mole) of n-propyl iodide was stirred and refluxed for five hoursand evaporated to dryness under reduced pressure. The residue waspartitioned between water and chloroform. The chloroform layer wasdried, filtered, and chromatographed on 110 g. of Grade HI alumina,eluting with chloroform. The product fractions (as determined by thinlayer chromatographic analysis) were combined, evaporated to dryness,taken up in ethanol, acidified with ethanolic hydrogen chloride, anddiluted with diethyl ether to give 1.6 g. of solid, M.P. 290 C. Thismaterial was recrystallized from ethanol-ether to yield trans-1,2,3,4,4a,5,10,10a-octahydro 1 propyl 5,5 dimethylbenzo [g] quinolin-7-olhydrochloride as an off-white crystalline solid, M.P. 300 C.; nmr(DMSO-d showed methyl singlets at 76 and 63 Hz.

EXAMPLE 10 e cted with diethyl ether, and the combined ether layers werewashed with water, dried, and filtered. The filtrate as acidified with aslight excess of ethanolic hydrogen chloride and filtered to give 4.3 g.of solid, M.P. 262268 C. Recrystallization of this product fromethanol-ether yielded 3.3 g. of cis-l-allyl-1,2,3,4,4a,5,10,10a-octahydro 5 ,5-dimethylbenzo[g] quinolin-7-ol hydrochloride as a tansolid which melted at 271273 C.; nmr. (DMSO-d methyl singlets at 77 and72 Hz.

A mixture of 2.3 g. oftrans-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo [g]quinolin-7-ol,0.8 g. of sodium bicarbonate, 30 m1. of dimethylformamide, and 1.3 g. ofallyl bromide was stirred and refluxed for one and one-half hours andthen evaporated to dryness under reduced pressure. The residue waspartitioned between water and chloroform. Spontaneous crystallizationoccurred in the chlorform layer. This product was collected on a filter.It weighed 2.2 g. and melted at 215222 C. By recrystallization of thissolid from dimethylformamide, washing with ethanol, and drying at 50 C.in vacuo, there was obtained 2.15 g. oftrans-1,2,3,4,4a,5,10,10aoctahydro-l-allyl 5,5dimethylbenzo[g]quinolin-7-ol, as an off-white solid which melted at2152l8 C.; nmr (TFAA) methyl singlets at 87 and 72 Hz.

' EXAMPLE 11 A mixture of 3.46 g. of 1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[g]quinolin-7-ol, 2.5 g. of 1-bromo-3- methyl-Z-butene,1.7 g. of sodium bicarbonate and'40 ml. of dimethyl formamide wasstirred and refluxed for three hours. The reaction mixture was filteredand methanol was used in a rinse. The filtrate, including the rinseliquid, was concentrated under reduced pressure and the resultingresidual product was partitioned between chloroform and water. Thechlorform layer was separated, washed with water, dried, treated withdecolorizing charcoal, and filtered. The filtrate was concentrated underreduced pressure to yield 5.5 g. of dark red syrup. This syrup wasdissolved in acetone and the solution was cooled. The crystalline solidwhich separated from solution was collected on a filter, washed withcold acetone, and dried at 70 C. There was thus obtained 3.5 g. ofproduct which melted at 168-172 C. By recrystallization of 2.0 g. ofthis product from acetone there was obtained 1.4 g. of1,2,3,4,4a,5,10,10a-octahydro-1-(3-methyl 2-butenyl)-5,5-dimethylbenzo[g] quinolin-7-ol as an olT-white crystalline solid, M.P. 170l73 C.

EXAMPLE 12 A mixture of 1.5 g. of cis-1,2,3,4,4a,5,10,10-octahydro-1-(3-methy1-2-butenyl) 5,5 dimethylbenzo[g] quinolin- 7-01 and 15 ml. ofacetic anhydride was heated on a steam bath for forty-five minutes. Thereaction mixture was concentrated under reduced pressure and the residuewas dissolved in diethyl ether. The ether solution was washed with acold, saturated aqueous sodium bicarbonate solution, dried, treated withdecolorizing charcoal, and filtered. The filtrate was concentrated toyield 1.6 g. of a syrup. This product was dissolved in 15 ml. of ethylacetate and acidified with ethereal hydrogen chloride. The crystallinesolid which precipitated was collected on a filter, washed with diethylether, and dried at 70 C. There was thus obtained 1.1 g. ofcis-1,2,3,4,4a,5,10,10aoctahydro-l-(3-methyl-2-butenyl) 5,5dimethyl-7-acetoxy-benzo [g] quinoline hydrochloride as a whitecrystalline solid, M.P. 251-252 C. (dec.).

EXAMPLE 13 A solution of 3.5 g. ofcis-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo [g] quinolin 7-01hydrobromide in 60 ml. of pyridine was stirred while 2.4 g. ofcyclopropanecarbonylchloride was added dropwise. Stirring was continuedthree hours after addition of the acid chloride was completed. Themixture was evaporated to dryness under reduced pressure and the residuewas partitioned between water and diethyl ether. The ether layer waswashed with dilute hydrochloric acid, saturated aqueous sodiumbicarbonate solution, dried, filtered, and evaporated to dryness underreduced pressure. There was thus obtained 3.7 g. of cis1,2,3,4,4a,5,10,10a octahydro-l-cyclopropanecarbonyl 5,5dimethyl-7-(cyclopropanecarb onyloxy) benzo [g] quinoline.

When 3.25 g. of trans-1,2,3,4,4a,5,10,10a-octahydro- 5,5-dimethylbenzo[g] quinolin 7 o1 hydrobromide was used in the above procedure insteadof the cis isomer, there was obtained as the product 3.06 g. oftrans-l,2,3,4, 4a,5,10,10a-octahydro 1- cyclopropanecarbonyl5,5-dimethyl-7- (cycloprop anecarb onyloxy benzo g] quinoline.

EXAMPLE 14 A solution of 3.7 g. ofcis-1,2,3,4,4a,5,10,10a-octahydro-l-cyclopropanecarbonyl 5,5dimethyl-7-(cyclopropanecarbonyloxy)benzo[g]quinoline in 40 ml. oftetrahydrofuran was added dropwise to an ice-cold, stirred suspension of0.8 g. of lithium aluminum hydride in ml. of tetrahydrofuran. After thisaddition was completed, the mixture was refluxed for eight hours. Aftercooling the reaction mixture, 1.6 ml. of water was added dropwise andthe mixture was then diluted with tetrahydrofuran and filtered throughFilter-Cel. The residue was washed with hot tetrahydrofuran and thefiltrate and wash were combined and evaporated to dryness under reducedpressure to give 3.0 g. of crude product. This material was taken up indiethyl ether and treated with a slight excess of ethanolic hydrogenchloride. The hydrochloride which precipitated was recrystallized fromethanol-ether to yield 1.1 g. ofcis-1,2,3,4,4a,5,10,10aoctahydro-l-cyclopropylmethyl 5,5dimethylbenzo[g] quinolin-7-ol hydrochloride as a white crystallinesolid, M.P. 267-269" C.; nmr (TFAA) showed methyl singlets at 87 and 80Hz.

Using 3.06 g. of trans-1,2,3,4,4a,5,10,10a-octahydro-1-cyclopropanecarbonyl 5,5dimethyl-7-(cyclopropanecarbonyloxy)-benzo[g]quinoline as the startingmaterial in the reduction procedure above instead of the correspondingcis isomer, there was obtained as the product 1.6 g. of trans1,2,3,4,4a,5,10,10a octahydro 1 cyclopropylmethyl 5,5 dimethylbenzo [g]quinolin-7-ol hydrochloride as a white crystalline solid, M.P. 266 C.(dec.); nmr (TFAA) showed methyl singlets at 87 and 73 Hz.

EXAMPLE 15 To a stirred mixture of 3.12 g. ofcis-1,2,3,4,4a,5,10,10aoctahydro-5,5-dimethylbenzo[g]quinolin-7-ol and60 ml. of pyridine cooled in an ice bath there was added dropwise asolution of 1.18 g. of dimethylcarbamyl chloride in 5 ml. of diethylether. Stirring and ice cooling were continued for ten minutes afterthis addition was completed, and then stirring without cooling wascontinued for three hours more. The crystalline precipitate which hadseparated was collected on a filter and washed with pyridine. Thefiltrate, including the wash liquid, was concentrated under reducedpressure and the residue thus obtained was partitioned between water andchloroform. The chloroform solution was washed with dilute hydrochloricacid, water, and saturated aqueous sodium bicarbonate solution and thendried, filtered, and concentrated under reduced pressure to yield 2.0 g.of a glassy residue. This residue was recrystallized first from acetoneand then from ethanol thus yielding 0.8 g. of cis-l,2,3,4,4a,5, 10,10aoctahydro 1 dimethylcarbamyl-5,5-dimethylbenzo[g]quinolin-7-ol as awhite crystalline solid which melted at 208-210 C.

EEXAMPLE 16 (A) Proceeding in a manner similar to that described abovein part F of Example 1, 41.2 g. of cis ethyl 1-benzyl oxycarbonyl2-(p-methoxybenzyl)-3-piperidinecarboxylate was interacted in a Grignardreaction with ethylmagnesium bromide (prepared from 12.2 g. of magnesiumturnings and 54.5 g. of ethyl bromide) to yield 41.8 g. of

cis 1benzyloxycarbonyl-Z-(p-methoxybenzyl)-a,a-diethyl-3-piperidinemethanol.

(B) Proceeding in a manner similar to that described above in part G ofExample 1, 17.5 g. of cis-l-benzyloxycarbonyl2-(p-methoxybenzyl)-u,a-diethyl-3-piperidinemethanol was converted tothe hydrochloride and catalytically hydrogenated in the presence ofpalladium-on-charcoal catalyst to yield 10.7 g. ofcis-2-(p-methoxybenzyl)- a,u-diethyl-3-piperidinemethanol.

(C) Proceeding in a manner similar to that described above in part H ofExample 1, 10.7 g. ofcis-2-(p-methoxybenzyl)-a,a-diethyI-S-piperidinemethanol was heated witha mixture of 55 ml. of glacial acetic acid and 11 ml. of concentratedsulfuric acid to yield 9.0 g. of a mixture of the cis and trans forms of1,2,3,4,4a,5,10,10a octahydro-7- methoxy 5,5 diethylbenzo[g]quinoline asa syrup. By chro'matographing this product on alumina, using a mixtureof chloroform and methanol in a volume/volume ratio of 96/ 4, there wasobtained 1.3 g. of cis-l,2,3,4,4a,5, 10,10a octahydro7-methoxy-5,S-diethylbenzo [g] quinoline as a syrup. This base wasconverted to the hydrochloride, a white crystalline solid which meltedat 193-195 C.

EXAMPLE 17 Proceeding in a manner similar to that described above inExample 7, 3.0 g. of cis-1,2,3,4,4a,5,10,10a-octahydro- 7methoxy-5,5-diethylbenzo[g]quinoline hydrochloride was heated with 30ml. of 48% hydrobromic acid to yield 2.4 g. of cis1,2,3,4,4a,5,10,10a-octahydro-S,S-diethylbenzo[g] quinolin-7-olhydrobromide as a white crystalline solid.

EXAMPLE 18 Proceeding in a manner similar to that described above inExample 10, 2.37 g. ofcis-1,2,3,4,4a,5,10,10a-octahydro-5,5-diethylbenzo [g]quin0lin-7-ol.hydrobromide. 0.92 g. of allyl bromide, and 1.2 g. of sodium bicarbonatewere interacted in 24 ml. of dimethylformamide to yield 1.3 g. of cis1,2,3,4,4a,5,10,10a octahydro-1-allyl-5,5-diethylbenzo[g]quinolin-7-olas a white crystalline solid, M.P. l30133 C. When recrystallized fromacetone this compound melted at 132-134 C.

(EXAMPLE 19 (A) A mixture of 9.8 g. of magnesium turnings, 12 g. ofbromobenzene, and an iodine crystal in 28 ml. of anhydrous diethyl etherwas stirred until there was evidence that the reaction had started. Then280 ml. of anhydrous diethyl ether was added, and 50.8 g. ofbromobenzene was dripped in at a rate sufficient to maintain refluxing.After this addition was completed, the reaction mixture was refluxed forthirty minutes. There was then added, with stirring, 12.0 g. of cisethyl l-benzyloxycarbonyl-Z- (p-methoxybenzyl)-3-piperidinecarboxylatein 400 ml. of anhydrous diethyl ether. The resulting reaction mixturewas refluxed for five hours and then quenched with dilute hydrochloricacid. The ether layer was separated, washed with 1 N sodium hydroxidesolution and with water, and filtered over anhydrous calcium sulfate.The filtrate was concentrated under reduced pressure to yield 50 g. ofcis 1 benzyloxycarbonyl-Z-(p-methoxybenzyl)-u,a-diphenyl 3piperidinemethanol as a crystalline residue. When a sample of thiscompound was recrystallized from ethanol there was obtained theethanolate,

as a white crystalline solid which melted at 110 C. (dec.).

(B) A mixture of 50 g. of cis-l-benzyloxycarbonyl-2-(p-methoxybenzyl)-tx.,a-diphenyl 3-piperidinemethanol, 250 ml. ofglacial acetic acid, and 50 ml. of concentrated sulfuric acid was heatedon a steam bath for ten minutes and then was poured over ice. Themixture was made basic byaddition of a 35 percent aqueous solution ofsodium hydroxide and extracted with diethyl ether. The ether extract waswashed twice with water, dried, treated with decolorizing charcoal, andfiltered. The filtrate was concentrated to yield 40 g. of a syrup. Thisproduct was taken up in 80 ml. of ethanol and concentrated under reducedpressure. The resulting residue crystallized slowly. The crystallinesolid was mixed with 40 ml. of ethanol, the mixture was filtered, andthe solid thus collected was washed with ethanol, the filtrate,including the Wash liquor, being retained. This first crop of crudeproduct weighed 2.1 g. The retained filtrate and wash liquor werecombined and concentrated under reduced pressure. The residue thusobtained was partitioned betweendiethyl ether and dilute phosphoricacid. The aqueous layer was separated, washed with diethyl ether, andmade basic with ammonium hydroxide. The oil which formed was extractedwith diethyl ether and the ether extract was washed with water, dried,treated with decolorizing charcoal, and filtered. The filtrate wasconcentrated to yield 26 g. of a syrup. By chromatographing on aluminausing benzene and chloroform, there was obtained from g. of this syrup asecond crop of crude product which weighed 3.2 g. This was combined withthe first crop and recrystallized twice from ethanol to yield 3.0 g. ofcis- 1,2,3,4,4a,5,10,10a octahydro 7-methoxy-5,5-diphenylbenzo [g]quinoline as a white crystalline solid which melted at 135l37 C.

EXAMPLE (A) Using a procedure similar to that described above in part Aof Example 1, 106 g. of diethyl (2-cyanoethyl)- malonate was interactedwith 21.9 g. of sodium hydride, and this product was interacted with77.5 g. of phenylacetyl chloride to yield 152 g. of crude diethyl(phenylacetyl) (2-cyanoethyl)malonate.

(B) Using a procedure similar to that described above in part B ofExample 1, 152 g. of crude diethyl (phenylacetyl)-(2-cyanoethyl)malonatewas catalytically reduced in the presence of platinum catalyst, and thereduction product treated was with hydrochloric acid to yield 104 g. ofcrude diethyl 2-benzyl-3,3-piperidinedicarboxylic hydrochloride as awhite crystalline solid which melted at l82184 C. (dec.). When purifiedby recrystallization from ethanolic hydrogen chloride solution and fromisopropyl alcohol, this compound melted at 188 C. (dec.).

By interaction of 38.6 g. of diethyl2-benzyl-3,3-piperidinedicarboxylate with 19.1 g. of p-toluenesulfonylchloride in the presence of 300 ml. of pyridine there was obtained 34.1g. of diethyl l-(p-toluenesulfonyl)-2-benzyl-3,3-piperidinedicarboxylate which melted at ll6-ll8 C.

By interaction of 40.4 g. of diethyl2-benzyl-3,3-piperidinedicarboxylate with 13.4 g. of ethyl chloroformatein the presence of aqueous sodium hydroxide solution and chloroformthere was obtained 35.5 g. of crude triethyl 2-benzyl-1,3,3-piperidinetricarboxylate as a white crystalline solid whichmelted at 72-76 C. A 5.0 g. portion was recrystallized from hexane toyield 4.0 g. of purified prodnot which melted at 7780 C.

(C) Proceeding in a manner similar to that described above in part C ofExample 1, 104 g. of crude diethyl 2- benzyl-3,3-piperidinedicarboxylatehydrochloride was interacted with 55.0 g. of benzyloxycarbonyl chlorideto produce 130 g. of crude diethyl l-benzyloxycarbonyl-Z-benzyl-3,3-piperidinedicarboxylate as an orange-colored oil. The purecompound was a white crystalline solid, M.P. 66-70 C. (dec.).

(D) Using a procedure similar to that described in part D of Example 1,130 g. of crude diethyll-benzyloxycarbonyl-2-benzyl-3,3-piperidinedicarboxylate washalf-hydrolyzed with 18.8 g. of 86 percent potassium hydroxide to yield76.6 g. of crude 1-benzyloxycarbonyl-Z-benzyl-3-carbethoxy-3-piperidinecarboxylic acid as a white crystalline solidwhich melted at 169 C. (dec.). When purified by recrystallization fromethanol, this compound melted at l82184 C. (dec.).

(E) Following a procedure similar to that described above in part B ofExample 1, 75.6 g. of crude l-benzyl- 20oxycarbonyl-2-benzyl-3-carbethoxy-3-piperidinecarboxylic acid wasdecarboxylated to yield 60.4 g. of crude ethyl 1benzyloxycarbonyl-2-benzyl-3-piperidinecarboxylate.

('F) Following a procedure similar to that described above in part F ofExample 1, 60.4 g. of crude ethyl1benzyloxycarbonyl-Z-benzyl-3-piperidinecarboxylate was interacted in aGrignard reaction with methylmagnesium iodide (prepared from 11.5 g. ofmagnesium and 67.5 g. of methyl iodide) to yield 53.1 g. of crudel-benzyloxycarbony1-2-benzyl-u,a-dirnethyl-3-piperidinemethanol.

(G) Following a procedure similar to that described above in part G ofExample 1, 53.1 g. of crude l-benzyl- -oxycarbonyl-2-benzyl-a,adimethyl-3-piperidinemethanol was converted to the hydrochloride andcatalytically hydrogenated in the presence of palladium-on-charcoalcatalyst to yield 20.3 g. of crude 2-benzyl-u,a-dimethyl-3-piperidinemethanol, M.P. 83-104 C.

(H) Hydrogen chloride was bubbled into a solution of 15.6 g. of2-benzyl-a,a-dimethyl-3-piperidinemethanol in m1. of nitrobenzene untilthe solution was acidic. The solution was cooled in an ice bath, and15.6 g. of aluminum chloride was added in small portions. After thisaddition was completed, the temperature of the reaction mixture wasallowed to rise to room temperature, and the mixture was stirred forthree hours and then poured into water. A large volume of diethyl etherwas added. The aqueous layer was separated and made strongly basic with35 percent sodium hydroxide solution and then extracted twice withdiethyl ether. The ether extracts were combined and washed with water,dried, and filtered. The filtrate was evaporated under reduced pressureto yield as a residue 13.0 g. of a crude mixture of the cis and transforms of 1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo [g]quinolinehydrochloride in an approximate cis/ trans ratio of 1.4/1. A 2.0 g.portion of this product was chromatographed on alumina, using achloroform-methanol mixture in a volume ratio of 96 to 4, to yield 0.3g. of cis-l,2,3,4,4a,5,l0,10a-octahydro-5,S-dimethylbenzo[g] quinolinehydrochloride as a White crystalline solid, M.P. 286-287 C. (dec.), andapproximately 1.3 g. of a cisrich mixture of the cis and transhydrochlorides.

EXAMPLE 21 (A) Using a procedure similar to that described above inExample 6, 6.99 g. of crude 2-benzyl-u,u-dimethyl-3- piperidinemethanolwas interacted with 5.73 g. of ptoluenesulfonyl chloride in 70 ml. ofpyridine at room temperature to yield 3.0 g. of 1-(p-toluenesulfonyl)-2-benzyl-u,u-dimethyl-3-piperidinemethanol which melted at 171-172 C.

(B) Using a procedure similar to that described above in Example 6, 46.9g. of l-(p-toluenesulfonyl)-2-benzyla,a dimethyl 3 piperidinemethanolwas heated with a mixture of 250 ml. of glacial acetic acid and 50 ml.of concentrated sulfuric acid to yield 30.3 g. of crude 1,2,3,4,4a,5,10,10a octahydro 1 (p toluenesulfonyl)5,5-dirnethylbenzo[g]quinoline which melted at 138-140 C. Byrecrystallization of this product from ethanol there was obtained 27.1g. of cis-1,2,3,4,4a,5,10,10a-octahydro-1-(p-toluenesulfonyl)-5,5-dimethylbenzo[g]quinoline as a whitecrystalline solid, M.P. 142-144 C.

(C) 28.0 g. of cis-1,2,3,4,4a,5,l0,l0a-octahydro-l-(ptoluenesulfonyl)5,5 dimethylbenzo[g]quinoline was reduced with 28.0 g. of lithiumaluminum hydride in 560 ml. of tetrahydrofuran to yield 13.0 g. ofcis-1,2,3,4,4a,5, 10,10a octahydro-5,S-dimethylbenzo[g]quinolinehydrochloride, identical with that described above in part H of Example20.

EXAMPLE 22 By interaction with a mixture of 10 ml. of formic acid and 10ml. of 35% aqueous formaldehyde solution, 4.3 g. ofcis-l,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[g] quinoline wasN-methylated to yield 2.1 g. of cis-1,2,3,4, 4a,5,l0,10aoctahydro-l,5,5-trimethylbenzo [g]quinoline as a clear liquid whichboiled at 75 C. at 0.05 mm. pressure.

EXAMPLE 23 By interacting 4.3 g. ofcis-l,2,3,4,4a,5,10,la-0ctahydro-5,5-dimethylbenzo[g]quinoline with 3.7g. of npropyl iodide in the presence of 1.9 g. of sodium bicarbonate and40 ml. of dimethylformamide in a procedure similar to that describedabove in Example 9, there was obtained 3.7 g. of1,2,3,4,4a,5,10,10a-octahydro-1-propyl- 5,5-dimethylbenzo[g]quinoline asa straw-colored liquid which boiled at 9099 C. at 0.05 mm. pressure.

EXAMPLE 24 Using a procedure similar to that described above in Example10, 2.5 g. of cis-1,2,3,4,4a,5,10,10a-octahydro- 5,5-dimethylbenzo[gquinoline hydrochloride was converted to the free base by treatment withammonia, and the free base was interacted with 1.33 g. of allyl bromidein the presence of 0.92 g. of sodium bicarbonate and ml. ofdimethylformamide to yield 1.7 g. of 1,2,3,4,4a,5, 10,10aoctahydro-l-allyl-5,5-dimethylbenzo[g]quinoline as a colorless oil whichboiled at 84 C. at 0.05 mm. pressure.

EXAMPLE 25 By interacting 4.3 g. of cis-1,2,3,4,4a,5,l 0,10a-octahydro-5,5-dimethylbenzo[g] quinoline with 2.3 g. ofcyclopropanecarbonyl chloride in pyridine in a manner similar to thatdescribed above in Example 13, there was obtained 5.0 g. ofcis-1,2,3,4,4a,5,10,10a-octahydro-l-cyclopropanecarbonyl-5,5-dimethylbenzo[g]quinoline. When this product was reduced with 1.5 g. of lithium aluminumhydride in ml. of tetrahydrofuran in a manner similar to that describedabove in Example 14, there was obtained 2.5 g. ofcis-1,2,3,4,4a,5,10,10a-octahydro-l-cyclopropylmethyl5,5-dimethylbenzo[g] quinoline as a clear liquid which boiled at 105 C.at 0.06 mm. pressure; n =1.5492.

EXAMPLE 26 (A) To a solution of sodium ethoxide obtained by dissolving0.7 g. of sodium in 110 ml. of ethanol there was added 144 g. of ethylp-methoxy-benzoylacetate (obtained by mixing ethyl p-methoxybenzoatewith sodium hydride and interacting the resulting mixture with ethylacetate). The resulting mixture was stirred for ten minutes and then34.2 g. of acrylonitrile was added, and the reaction mixture was allowedto stand overnight at room temperature. The reaction mixture was thenconcentrated under reduced pressure. The residue was taken up in diethylether, washed with dilute acetic acid and with water, dried, andfiltered. The filtrate was concentrated to yield a clear yellow oilwhich was vacuum-distilled. The fraction distilling at 180-198" C. at0.2 mm. pressure weighed 144.6 g. and had n =1.5341. This product wasethyl a-(p-methoxybenzoyl)-'y-cyanobutyrate.

(B) 144 g. of ethyl a-(p-methoxybenzoyl)-' -cyanobutyrate was diluted toa volume of 1400 ml. with glacial acetic acid, platinum oxide catalystwas added and the mixture was catalytically hydrogenated for eighthours. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure. The resulting residue waspartitioned between diethyl ether and dilute hydrochloric acid (85 ml.of concentrated hydrochloric acid in 500 ml. of water). The aqueouslayer was separated and made basic with ammonium hydroxide, adding iceto cool the solution, and extracted twice with diethyl ether. The etherextract was washed with water, dried, and filtered. The filtrate wasconcentrated to yield 108 g. of residue which crystallized. This solidwas dissolved in boiling hexane and the solution was cooled. The solidwhich separated from solution was collected on a filter and washed withhexane. There was thus obtained 94.4 g. of ethyl2-(p-methoxyphenyl)-3-piperidinecarboxylate as a white crystalline solidwhich melted at -70 C. Purification of a one gram portion byrecrystallization from 22 acetone yielded 1 g. of this product whichmelted at 7072 C.

(C) Proceeding in a manner similar to that described in part F ofExample 1, 66.7 g. of ethyl Z-(p-methoxyphenyl)-3-piperidinecarboxylatewas reacted in Grignard reaction with methylmagnesium iodide (obtainedfrom 36.4 g. of magnesium turnings and 213 g. of methyl iodide) to yield46.7 g. of 2-(p-methoxyphenyl)-a,adimethyl-3-piperidinemethanolhydrochloride as a crystalline solid which melted at 246248 C.

(D) To a stirred solution of 46.7 g. of2-(p-methoxyphenyl)-a,a-dimethyl-3-piperidinemethanol in 450 ml. ofnitrobenzene there was added 50 g. of aluminum chloride in smallportions. After this addition was completed, the reaction mixture wasstirred for six hours and allowed to stand overnight. The reactionmixture was poured into ice water. The mixture was shaken thoroughly andthen the nitrobenzene layer was removed. The aqueous layer was acidifiedby addition of concentrated hydrochloric acid and filtered. The filtratecontained some nitrobenzene, which was removed, and the aqueous layerwas washed twice with diethyl ether and then made slightly basic byaddition of ammonium hydroxide. The precipitate which formed wascollected on a filter and washed thoroughly with diethyl ether. Therewas thus obtained 28.2 g. of crude 1,2,3,4,4a,9bhexahydro-7-methoxy-5,5-dimethyl- 5H-indeno[l,2,b]pyridine hydrochlorideas a white crystalline solid which melted at 280-283 C. Purification ofa one gram portion by recrystallization from methanoldiethyl etheryielded 0.6 g. of this product which melted at 289-292 C.

EXAMPLE 27 Using a procedure similar to that described above in Example7, 27.4 g. of crude 1,2,3,4,4a,9b-hexahydro-7- methoxy-5,5-dimethyl5H-indeno[1,2,b]pyridine hydrochloride was hydrolyzed by heating with150 ml. of 48% hydrobromic acid to yield 24.5 g. of1,2,3,4,4a,9b-hexahydro-5,5-dimethyl 5H-indeno[1,2,b]pyridin-7-olhydrobromide which melted at 284-287" C. (dec.). Treatment of 7.5 g. ofthis salt with ammonium hydroxide yielded 5.5 g. of the correspondingfree base which melted at EXAMPLE 28 To a stirred mixture of 6.5 g. of1,2,3,4,4a,9b-hexahydro-5,S-dimethyl-SH-indeno[1,2,b]pyridin-7-ol and100 ml. of pyridine there was added dropwise 6.8 g. ofcyclopropanecarbonyl chloride and the reaction mixture was stirred foreight and one-half hours and then allowed to stand overnight at roomtemperature. The reaction mixture was filtered and the solid thuscollected was washed twice with pyridine. The filtrate and wash liquorwere combined and concentrated under reduced pressure, and the resultingresidue was partitioned between water and diethyl ether. The ether layerwas washed successively with dilute hydrochloric acid, saturated aqueoussodium bicarbonate solution, and water, and then dried and filtered. Thefiltrate was concentrated under reduced pressure to yield 102 g. ofcrude 1,2,3,4,4a,9b-hexahydro- 1 (cyclopropanecarbonyl) 7(cyclopropanecarbonyloxy)-5,5-dimethyl-5H-dimethyl 5Hindeno[1,2,b]pyridine. When a 0.4 g. portion was recrystallized fromhexane there was obtained 0.3 g. of this product which melted at IDS-109C.

EXAMPLE 29 A solution of 9.8 g. ofl,2,3,4,4a,9b-hexahydro-l-cyclopropanecarbonyl 7 cyclopropanecarbonyloxy5,5- dimethyl 5H indeno[l,2,b] pyridine in m1. of tetrahydrofuran wasadded dropwise to 2.1 g. of lithium aluminum hydride covered with 20 ml.of tetrahydrofuran cooled in ice. After this addition was completed, thereaction mixture was refluxed for six hours, allowed to stand overnightat room temperature, and then 4.2 ml. of water was added dropwise. Themixture was diluted with tetrahydrofuran to a volume of 800 ml.,diatomaceous silica filter aid was added, and the mixture was boiled andfiltered. The residue thus collected was washed with hottetrahydrofuran, and the filtrate and wash liquor were combined andconcentrated under reduced pressure to yield 7.2 g. of a glassy residue.This residue was crystallized from acetone to yield 3.8 g. oftrans-l,2,3,4,4a,9b

hexahydro 1 cyclopropylmethyl 5,5 dimethyl-5H- indeno[l,2,b]pyridin-7-olas an off-white crystalline solid which melted at l88l90 C.

EXAMPLE 30 A mixture of 5.0 g. of cis-1,2,3,4,4a,5,10,IOa-octahydro 5,5dimethylbenzo [g] quinoline hydrochloride, 3.7

g. of bromoacetaldehyde dimethyl acetal, 3.4 g. of sodium EXAMPLE 31Proceeding in a manner similar to that described above in Example 30,5.6 g. of trans-l,2,3,4,4a,5,10,10a-octahydro 7 methoxy 5,5dimethylbenzo[g1quinoline hydrochloride, 3.7 g. of bromoacetaldehydedimethyl acetal, and 3.4 g. of sodium bicarbonate were interacted in 50ml. of dimethylformamide to yield 5.0 g. of trans-1,2,3, 4,4a,5,l0,laoctahydro 7 methoxy 5,5-dimethylbenzo[g]quinoline-l-acetaldehydedimethyl acetal hydrochloride as a white crystalline solid which meltedat 185 C. (dec.).

EXAMPLE 32 (A) A solution of 11.6 g. of cis-1-benzyloxycarbonyl- 2(p-methoxybenzyl) 3 piperidinecarboxylic acid in 55 ml. of 30% hydrogenbromide in acetic acid was allowed to stand at room temperature forone-half hour, and then 5 ml. of diethyl ether was added and theprecipitate which formed was filtered, washed with diethyl ether, anddried under reduced pressure over solid sodium hydroxide. There was thusobtained 9.0 g. of cis 2-(pmethoxybenzyl) 3 piperidinecarboxylic acidhydrobromide, M.P. 243-245 C. (dec.).

(B) A mixture of 9.9 g. of cis 2 (p-methoxybenzyl)-3-piperidinecarboxylic acid hydrobromide, 7.6 g. of sodiurn bicarbonate,3.8 g. of benzyl chloride, and 100 ml. of dimethy'lformamide is stirredand refluxed for two hours. The reaction mixture is concentrated underreduced pressure, and the resulting residue is taken up in 100 ml. ofwater. By acidification with ml. of N hydrochloric acid, there isproduced cis-l-benzyl-Z-(p-methoxybenzyl)-3- piperidinecarboxylic acid.

(C) A solution of 33.9 g. of cis 1-benzyl-2-(pmethoxybenzyl) 3piperidinecarboxylic acid in 340 ml. of diethyl ether is stirred at roomtemperature while 200 ml. of l M methyl lithium is added dropwise. Afterthis addition is completed, the reaction mixture is stirred and refluxedfor four hours and poured over ice. The ether layer is separated andwashed with 100 ml. of saturated aqueous sodium bicarbonate solution,dried, and filtered. The filtrate is concentrated to yield cis-3- acetyll benzyl 2 (p-methoxybenzyl)piperidine.

(D) To the Grignard reagent prepared from 2.4 g. of magnesium turningsand 15.7 g. of bromobenzene in diethyl ether there is added dropwise anethereal solution of 33.7 g. ofcis-3-acetyl-l-benzyl-2-(p-methoxybenzyl) piperidine. After thisaddition is completed, the reaction mixture is stirred and refluxed forfour hours and poured 24 into aqueous ammonium chloride solution. Theether layer is separated, dried, and filtered. The filtrate isevaporated to dryness under reduced pressure to yield cis-l-benzyl- 2(p-methoxybenzyl)-a-methyl-a-phenyl 3 piperidinemethanol.

(E) A solution of 41.5 g. ofcis-1-benzyl-2-(p-methoxybenzyl)-a-methyl-a-phenyl 3 piperidinemethanolin 8.3 ml. of concentrated hydrochloric acid is diluted withdimethylformamide to a volume of 400 ml. and catalytically hydrogenatedunder 10 atmospheres of hydrogen in the presence of palladium-on-carboncatalyst. The catalyst is removed by filtration and the solvent isevaporated from the fi'ltrate under reduced pressure. The resultingresidue is taken up in ethanol and diluted with diethyl ether to yieldcis 2 (p-methoxybenzyl)- x-methyl-a-phenyl-3- piperidinemethanol.

(F) Using a procedure similar to that described above in part H ofExample 1, cis-Z-(p-methoxybenzyl)-;amethyl-a-phenyl 3piperidinemethanol is cyclized to yield 1,2,3,4,4a,5,10,10a octahydro 7methoxy 5- methyl 5 phenylbenzo [g]quinoline. By N-alkylation of thiscompound with allyl bromide there is obtained 1,2,3,4,4a,5,10,10aoctahydro 7 methoxy 5-methyl 5-phenylbenzo[g]quinoline. Cleavage of thisether with concentrated hydrobromic acid yields1,2,3,4,4a,5,10,10aoctahydro 1 ally'l 5 methyl-5-phenylbenzo[g]quinolin-7-ol.

EXAMPLE 33 Following the procedure described above in Example 10, butusing 1,3 dichloro l propene instead of allyl bromide, there is obtainedas the product l,2,3,4,4a,5, 10,10a octahydro l (3chloroallyl)-5,5-dimethylbenzo [g] quinolin-7-ol.

EXAMPLE 34 Following the procedure described above in Example 10, butusing 3-cyanoallyl bromide instead of allyl bromide, there is obtainedas the product l,2,3,4,4a,5,10,10a-octahydro 1 (3 cyanoallyl) 5,5dimethylbenzo[g] quinolin-7-ol.

EXAM PLE 3 5 Following the procedure described above in Example 1, butstarting with p-chlorophenylacetyl chloride instead ofp-methoxyphenylacetyl chloride, there are obtained as the successiveintermediate products in the reaction sequence: diethyl (pchlorophenylacetyl) (2 cyanoethyl)- malonate; diethyl2-(p-chlorobenzyl)-3,3-piperidinedicarboxylate; 1benzyloxycarbonyl-Z-(p-chlorobenzyl)-3,3- piperidinedicaboxylate; 1benzyloxycarbonyl-2-(p-chlorobenzyl)-3-carbethoxy-3-piperidinecarboxylicacid; ethyl 1- benzyloxycarbonyl-Z-(p-chlorobenzyl) 3piperidinecarboxylate; and l-benzyloxycarbonyl-2-(p chlorobenzyl)-a,a-dirnethyl-3-piperidinemethanol, and as the cyclization product1,2,3,4,4a,5,10,l0a-octahydro 7 chloro-5,5-dimethylbenzo[g] quinoline.When this cyclization product is N-alkylated with n-propyl iodide thereis obtained 1,2,3,4,4a,5,10,10a octahydro 1 propyl 7 chloro- 5 ,5-dimethylbenzo[g] quinoline.

[EXAMPLE 36 A mixture of 2.6 g. oftrans-enriched-l-benzyloxycarbonyl-Z-(p-methoxybenzyl) a,udimethyl-3-piperidinemethanol, 13 ml. of glacial acetic acid, and 2.6ml. of concentrated sulfuric acid was heated on a steam bath for sixminutes, poured into water, and extracted with diethyl ether. Theaqueous layer was made basic with concentrated ammonium hydroxide andextracted with diethyl ether. The ether layer was washed with water,dried, and filtered, and the filtrate was evaporated to dryness underreduced pressure to give 0.8 g. of a mixture of the cis and trans formsof crude product. The nuclear magnetic resonance spectrum showedapproximately 7 0% cis and 30% trans.

EXAMPLE 37 A mixture of 3 mg. of trans-Z-(p-methoxybenzyl)- 02,0:dimethyl 3 piperidinemethanol hydrochloride, 280 mg. of powderedpotassium carbonate, 0.1 ml. of p-Lfluoronitrobenzene and 2.5 ml. ofdimethyl sulfoxide was stirred and heated on a steam bath for one hourand poured into water and the mixture was extracted with diethyl ether.The ether extract was washed twice with water, dried, and filtered, andthe [filtrate was evaporated to dryness under reduced pressure to give340 mg. of crude product. A thin layer chr-omatogram showed an intenseyellow spot at R =0.36 (chloroform with 2% of methanol). This product,which was trans-2-(p-methoxybenzyl)-a,a-dimethyl-l-(p-nitrophenyl) 3piperidinemethanol, was isolated by preparative thin layerchromatography, and neither it nor its hydrochloride could be obtainedcrystalline; IR (CHCI 3600 (OH), 1310 (N0 1250 and 1030 (ether), and 820cm.- (1,4-disubstituted benzene).

EXAMPLE 38 (A) A mixture of 20 g. of neutral material recovered from thehydrogenolysis of cis l-benzyloxycarbonyl-2-(pmethoxybenzyl)-u,a-dimethyl 3 piperidinemethanol and which had stoodfor several months, 2 g. of palladium-on-carbon catalyst, and 200 ml. ofethanol was shaken under 50 p.s.i. of hydrogen until uptake ceased. Thereaction mixture was filtered, and the collected solid was rinsed withethanol. The filtrate and rinse were combined and evaporated to drynessunder reduced pressure. The residue was partitioned 'between dilutehydrochloric acid and diethyl ether. The aqueous layer was washed withether, made basic with concentrated ammonium hydroxide, and extractedwith diethyl ether. The ether extract was dried and filtered. A thinlayer chromatogram (silica, chloroform/ 3% isopropylamine) showed fivecompounds, R 0.36 (cis carbinol, weak), 0.41 (trans carbinol, trace),0.50 (strong), 0.53 (moderate), and 6.77 (trace). Treatment of thefiltrate with a slight excess of ethereal hydrogen chloride causedprecipitation of a gummy mass. The supernatant liquid was decanted, andthe gum was dissolved in hot ethanol. Cooling for several hours at 0" C.gave 9.1 g. of 2-(p-methoxybenzyl)-3- isopropylidenepiperidine. This wastwice recrystallized from ethanol-diethyl ether to give material whichmelted 255-257 C. and gave a single spot on a thin layer chromatogramwith R; 0.50, IR (KBr) 1660 (tetrasubstituted double bond) and 820 cm.-(1,4-disubstituted benzene); NMR (CD01 413 (A B q, 4), 235 (t. 1 1:7c.p.s., 223 (s. 3), 196 (broad singlet, 3), 87 (d. 3), 1:1 c.p.s.,200-50 (broad envelope, 9).

(B) A mixture of 3.8 g. (0.013 mole) of 2-(p-methoxybenzyl) 3isopropylidenepiperidine hydrochloride, 20 ml. of glacial acetic acid,and 4 m1. of concentrated sulfuric acid was heated on a steam bath forone hour, poured into water, made basic with concentrated ammoniumhydroxide, and extracted with diethyl ether. The ether extract waswashed with water, dried, and filtered, and the filtrate was evaporatedto dryness under reduced pressure to give 3.4 g. (100%) of crudeproduct. A thin layer chromatogram showed thatcis-l,2,3,4,4a,5,10,10aoctahydro-7-methoxy-5,5-dimethylbenzo[g]quinoline was the major product and the corresponding trans isomer was aminor product. A nuclear magnetic resonance spectrum of this crudeproduct confirmed this and gave the cisztrans ratio as 80:20.Furthermore, a crystalline hydrochloride could be obtained which, aftertwo recrystallizations from ethanol-diethyl ether, was identical in allrespects (R infrared spectrum, melting point and mixed melting point)with the cis product obtained by cyclization of the correspondingcarbinol.

(C) -A mixture of 2.8 g. of 2 (p-methoxybenzyl)-3-isopropylidenepiperidinehydrochloride, 0.8 ml. of 35% aqueousformaldehyde solution, 1.4 ml. of triethylamine,

and ethanol to a total volume of 50 ml. was shaken at room temperatureunder 50 p.s.i. of hydrogen. The theoretical quantity of hydrogen wasconsumed in one hour. The reaction mixture was filtered and the residuethus collected was rinsed with a small amount of ethanol. The filtrateand rinse were combined and evaporated to dryness under reduced pressureand the residue was partitioned between dilute ammonium hyrroxide anddiethyl ether. The ether layer was washed with water, dried, andfiltered, and the filtrate evaporated to dryness under reduced pressureto give 1.9 g. of l-methyl-Z-(pmethoxybenzyl) 3 isopropylidenepiperidineas a syrup. This was taken up in 50 ml. of diethyl ether and treatedwith a slight excess of ethereal hydrogen chloride to precipitate a gum.Addition of 5 ml. of isopropyl alcohol and trituration causedcrystallization. Recrystallization from 5 ml. of isopropyl alcohol and50 ml. of diethyl ether afiorded the pure compound which melted at 179-183 0.; IR (KBr) 1670 cut- (tetrasubstituted double bond); NMR (of base,CDCI 147 (s. 3); 93 (s. 3); 63 (d. 3, J=12 c.p.s.).

(D) A mixture of 1.0 g. of 2-(p-methoxybenzyl)-3-isopropylidenepiperidine hydrochloride, 1.1 1g. of powdered potassiumcarbonate, 10 ml. of dimethyl sulfoxide, and 0.4 ml. ofp-fiuoronitrobenzene was stirred and heated on a steam bath for onehour. The reaction mixture was then poured into water and the water wasdecanted from the precipitated gum. The gum was washed with severalportions of water and then taken up in diethyl ether, and the ether waswashed with several portions of water. The ether was dried and filtered,and the filtrate was evaporated to dryness under reduced pressure toyield l-(pnitrophenyl) 2 (p methoxybenzyl) 3 isopropylidenepiperidine asa residue. Neither the residue nor its hydrochloride could be induced tocrystallize, although only one component could be observed on thin layerchromatographic analysis using several developing systems on both silicagel and alumina. The nuclear magnetic resonance spectrum (CDCl of thecrude residue showed: 439 (A B 410 (A B 295 (t. 1, 1:7 c.p.s.), 222 (a.3), 172 (d. 2, 1:7 c.p.s.), 95 (s. 3), 76 (d. 3, J=12 c.p.s.). Theultraviolet spectrum (95% ethanol) showed: 272 s. (.6 41000), 286 s. (e3500), 400 m. (e 16300); lit, p-methylanisole 277 (e 2100), 284 (e1800); N,N-dimethyl-p-nitroaniline 395 (6 20000).

(E) A mixture of 1.9 g. of2-(p-methoxybenzyl)-3-isopropylidenepiperidine hydrochloride, 1.7 g. ofp-nitro'benzenesulfonylchloride, 40 ml. of chloroform, and 2.4 ml. oftriethylamine was allowed to stand in a closed vessel at roomtemperature for twenty-four hours. The reaction mixture was then washedwith water, dilute hydrochloric acid, and saturated aqueous sodiumbicarbonate solution, dried, and filtered, and the filtrate wasevaporated to dryness under reduced pressure to give 3.5 g. ofl-(p-nitrobenzenesulfonyl)-2-(p-methoxybenzyl) 3isopropylidenepiperidine as a syrup. This material was taken up in 35ml. of hot ethanol and the solution allowed to cool. After filtrationand washing the collected product with ethanol and drying under reducedpressure at 50 C., there was obtained 2.4 g. of the pure product whichmelted at 114l16 C.; IR (KBr) 1670 (tetras-ubstituted double bond), 1540and 1350 (N0 and 1350 and 1150 2)- The following are furtherillustrative examples of the compounds of Formula I of this inventionwhich are obtained in the manner taught hereinabove:

1,2,3 ,4,4a,5,l0,10a-octahydro-l-cyclohexylmethyl- 7methanesulfonamido-5,5 -dimethylbenzo[g] quinoline.

1,2,3,4,4a,5,10,lOa-octahydro-l-propargyl-7 acetamido-S-methyl-S-phenylb'enzo [g] quinoline.

1,2,3,4,4a,5,10,10a-octahydro-1-cyclopropyl-7-trifluoromethoxy-5,5-dimethylbenzo[g] quinoline.

1,2,3,4,4a,5,1=0, IOa-octahydro-l-(cyclopentene-2-yl)-7-trifluoromethyl-5 -methy1-5 -ethylb enzo [g] quinoline.

1,2,3,4,4a,5,10,1 a-octahydro-1-(3,3-dichloroallyl)- 7-3-pyridinecarbonyloxy) ,5 -diphenyl'benzo- [g] quinoline.

1,2,3 ,4,4a,9b-hexahydro-1-propyl-5,5-dimethyl-5H- indeno[ 1,2,bpyridin-7-ol.

1,2,3 ,4,4a,9b-hexahydro- 1-a1lyl-5,5- dimethyl-SH-indeno[1,2,b]pyridin-7-ol.

1,2,3,4,4a,9b-hexahydro- 1- (3-chloroallyl) -5 ,5 -diphenyl- 5H-indeno[1,2,b] pyridin-7-ol.

1,2,3 ,4,4a,9b-hexahydro- 1- (cyclopenten-3-yl) -7-ethanesulfonamido-5-methyl-5-ethyl-5H-indeno- 1,2;b] pyridine.

l,2,3,4,4a,9b-hexahydro-1- (2-methyl-3-cyanoallyl)--.7-trifluoromethoxy-5-propyl-5-pheny1-5H- indeno 1 ,2,'b] pyridine.

1,2,3,4,4a,9b-hexahydrol- (cyclobutyl) -7-bromo- 5,5-dimethyl-5H-indeno[ 1,2,b] pyridine.

As indicated hereinabove, the l,2,3,4,4a,5,l0,IOa-octahydro 1-(Y )-7-(Y)-S-(Y )-5-(Y )-benzo[g]quinolines and 1,2,3,4,4a,9b hexahydro 1-(Y)-7-(Y )-5-(Y )-5- (Y )-5H-indeno[1,2,b] pyridines of this invention areuseful as antagonists of strong analgesic agents such as meperidine andmorphine. Generally speaking, the analgesic antagonist activity resideslargely or entirely in cis form, the trans form ordinarily being eitherof low activity or inactive. Thus, when tested in rats by a modifiedDAmour-Smith thermal stimulus test procedure, the compounds of Formula Iwere found to be antagonists of the analgesic activity of morphine andmeperidine. In this test procedure, when the compounds of Formula I wereadministered prior to or simultaneously with administration or morphineor meperidine, the expected analgesic eifect of the latter was decreasedwith increasing dosage levels of the former to a point where noanalgesic elfect was obtained. And when the new compounds wereadministered after the administration of morphine or meperidine, theanalgesic eifect was diminished or terminated, depending on the dosagelevels involved. For example representativecompounds of this invention,each in the form of an aqueous solution of the lactic acid acid-additionsalt, were administered subcutaneously to rats to determine the dosagelevel, in terms of weight of antagonist per kilogram of body weight ofthe animal, which caused reduction of the analgesic eifect of a 60rug/kg. dose of meperidine hydrochloride by approximately 50 percent ormg./ kg.

dose of morphine sulfate, so that the analgesic eifect produced by thecombination of'the antagonist and the meperidine hydrochloride or themorphine sulfate was substantially the same as the analgesic eifectproduced by a 30 mg./kg. dose of meperidine hydrochloride alone or 7.5mg./kg. of morphine sulfate alone, respectively. Representative testresults thus obtained were as follows:

Mg./kg., versus We claim:

1. A compound of the group consisting of 1-(Q)-2- [p-(Y)-phenyl-X-]-3-piperidinecarboxylic acid, 1-(Q)-2- [p-(Y)-phenyl-X]-3,3-piperidinedicarhoxylic acid, and lower alkyl esters ofsaid acids, wherein X is CH or a valence bond; Q' is benzyl orbenzyloxycarbonyl; Q is hydrogen, lower alkyl containing l-6 carbonatoms, benzyl, or benzyloxycarbonyl and Y is hydrogen, lower alkylcontaining 1-4 carbon atoms, halo, trifluoromethyl, and lower alkoxycontaining 1-4 carbon atoms. 2. 1 (Q' -2- [p- (Y -pheny1-X-] -3-piperidinecarboxylic acid and lower alkyl esters thereof according toclaim 1 wherein X is CH Q is benzyloxycarbonyl, and Y is lower alkoxy.

3. A compound according to claim 1 wherein X is a valence bond.

References Cited Albertson, I. Am. Chem. Soc. 72, 2594-9 (1950). Pitreet al., Farmaco Ed. Sci. 17, 130-40 (1962): [C.A.

57: 165489 supplied, original unavailable].

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,639,u11DATED February 1, 1972 INVENTOR(S) Noel F. Albertson and William F.Michne It is certified that error appears in the above-identified patentand that said Letters Patent are hereby corrected as shown below:

Column 5, lines 20-21, "cycloalkanecarbonyloxy,

cyclobutanecarbonyloxy" should read --cyc1oa1kanecarbony1oxy there areincluded for example cyclopropanecarbonyloxy,

cyclobutanecarbonyloxy.

Signed and Scaled this [SEAL] A ttes t:

twenty-third D 3) 0f December I 9 75

